(1-azinone)-substituted pyridoindoles

ABSTRACT

Substituted pyridoindoles for incorporation in pharmaceutical compositions employed in the treatment of various diseases correspond to formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1  is H or optionally substituted alkyl; R 2 , R 3 , R 4  are each independently selected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF 3 , and —CN; G is —CR 12 R 13 —NR 5 — or —NR 5 —CR 12 R 13 ; R 5 ; is H, optionally substituted alkyl, optionally substituted heterocycle, —C(═O)—R 6 , —C(═O)—O—R 7 , or —C(═O)—NR 19 R 20 ; R 6  and R 7  are each optionally substituted alkyl or optionally substituted heterocycle; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 19  and R 20  are each independently selected from H or optionally substituted alkyl; R 14  and R 15  are each independently H or halogen; L is —CH 2 —O—, —CH 2 CH 2 —, —CH═CH— or a bond; and B is aryl or heteroaryl or cycloalkyl; with the proviso that, when L is a direct bond, B cannot be unsubstituted heteroaryl or heteroaryl monosubstituted with fluorine.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. ProvisionalApplication Ser. No. 61/020,530, filed Jan. 11, 2008, and U.S.Provisional Application Ser. No. 61/048,677, filed Apr. 29, 2008, thedisclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to human melanin-concentrating hormone (MCH₁)receptor-selective antagonists substituted pyridoindoles that are usefulfor treating obesity, to pharmaceutical compositions comprising thesecompounds, and to methods for the treatment of obesity, anxiety,depression, and psychiatric disorders in a mammal.

BACKGROUND OF THE INVENTION

Obesity and the multitude of co-morbidities associated with obesity suchas diabetes, dyslipidemia, coronary heart disease, and certain cancersare a major concern for public health. The currently availablepharmaceutical therapies for the treatment of obesity have limitedefficacy and side effects that limit their use. Thus, there is asignificant medical need for better pharmacotherapy for obesity.

Melanin-concentrating hormone (MCH) has been identified as an orexigenicpeptide that exerts an effect on food intake and body weight regulation.MCH is a cyclic 19 amino acid neuropeptide expressed in the zona incertaand lateral hypothalamus in response to both energy restriction andleptin deficiency. MCH is known to stimulate feeding when injected intothe lateral ventricle of rats and the mRNA for MCH is upregulated in thehypothalamus of genetically obese mice (ob/ob) and in fasted control andob/ob animals. In addition, animals treated with MCH show increases inglucose, insulin and leptin levels, mimicking human metabolic syndrome(Gomori, A. Chronic infusion of MCH causes obesity in mice Am. J.Physiol. Endocrinol. Metab. 284, E583, 2002). Mice lacking MCH arehypophagic and lean with increased metabolic rate, whereas animalsover-expressing MCH gain excess weight on both standard and high fatdiets. MCH is thought to have effects on other nervous system functionsas well (Rocksz, L. L. Biological Examination of Melanin ConcentratingHormone 1: Multi-tasking from the hypothalamus Drug News Perspect 19(5),273, 2006). An orphan G-protein coupled receptor (GPCR) was recentlyidentified as a receptor for MCH. Disruption of the binding between MCHand the MCH receptor, i.e. MCH antagonism, may thus be used tocounteract the effects of MCH (McBriar, M. D. Recent advances in thediscovery of melanin-concentrating hormone receptor antagonists Curr.Opin. Drug Disc. & Dev. 9(4), 496, 2006).

SUMMARY OF THE INVENTION

In accordance the present invention, there is provided a compound offormula (I)

whereinR¹ is H or optionally substituted alkyl;R², R³, R⁴ are each independently selected from H, —O-alkyl, —S-alkyl,alkyl, halo, —CF₃, and —CN;

G is —CR¹²R¹³—NR⁵— or —NR⁵—CR¹²R¹³;

R⁵ is H, optionally substituted alkyl, optionally substitutedheterocycle, —C(═O)—R⁶, —C(═O)—O—R⁷, or —C(═O)—NR¹⁹R²⁰;R⁶ and R⁷ are each optionally substituted alkyl or optionallysubstituted heterocycle;R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁹ and R²⁰ are each independently selectedfrom H or optionally substituted alkyl;R¹⁴ and R¹⁵ are each independently H or halogen;L is —CH₂—O—, —CH₂CH₂—, —CH═CH— or a bond; andB is aryl or heteroaryl or cycloalkyl;with the proviso that, when L is a direct bond, B cannot beunsubstituted heteroaryl or heteroaryl monosubstituted with fluorine.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds represented byformula (I) above may be substituted derivatives either oftetrahydro-α-carboline, where G is —CR¹²R¹³—NR⁵—, or oftetrahydro-γ-carboline, where G is —NR¹²—CR¹³R¹³—. In some embodimentsof the invention, G is —CH₂—NR⁵—; in other embodiments, G is —NR⁵—CH₂—.In accordance with some embodiments of the invention, R¹ is H.

In accordance with other embodiments of the invention, R⁵ is alkyl, forexample, methyl or ethyl.

In accordance with some embodiments of the invention, R⁵ is H. In otherembodiments, R⁵ is optionally substituted alkyl. In some embodiments, R⁵is selected from methyl, ethyl, 2-propyl, 2-hydroxyethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,2-oxo-2-(pyrrolidin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl and(S)-pyrrolidin-2-ylmethyl. In other embodiments, R⁵ is optionallysubstituted heterocycle. In some embodiments, R⁵ is selected frompiperidin-4-yl and 1-methylpiperidin-4-yl. In other embodiments, R⁵ is—C(═O)—R⁶. In other embodiments, R⁵ is —C(═O)—O—R⁷.

In some embodiments, R⁶ and R⁷ are each optionally substituted alkyl,for example, methyl, 2-propyl, 2-(pyrrolidin-1-yl)-ethyl,pyrrolidin-1-ylmethyl, and dimethylaminomethyl. In some embodiments, R⁶is optionally substituted heterocycle, for example, pyrrolidin-3-yl,(R)-pyrrolidin-2-yl, (S)-pyrrolidin-2-yl, 1-methylpyrrolidin-3-yl,(R)-1-methylpyrrolidin-2-yl and (S)-1-methylpyrrolidin-2-yl.

In accordance with some embodiments of the invention, the compound hasthe

structure

In accordance with other embodiments of the invention, the compound hasthe

structure

In accordance with some embodiments of the invention, the L is a bond.In accordance with other embodiments of the invention, L is —CH₂—O—. Inaccordance with some embodiments of the invention, L is —CH₂CH₂—. Inaccordance with other embodiments of the invention, L is —CH═CH—.

In accordance with some embodiments of the invention, B is aryl, forexample, phenyl. In accordance with other embodiments of the invention,B is heteroaryl, for example, pyridinyl. In some embodiments, B ispyridin-2-yl or pyridin-3-yl. In other embodiments, B is pyridazinyl,for example, pyridazin-3-yl. In some other embodiments, B ispyrimidinyl, for example, pyrimidin-5-yl or pyrimidin-2-yl. Inaccordance with other embodiments of the invention, B is cycloalkyl, forexample, cyclohexyl.

In accordance with some embodiments of the invention, R², R³ and R⁴ areeach H. In accordance with other embodiments of the invention, two ofR², R³ and R⁴ are H, and the other of R², R³ and R⁴ is selected fromtrifluoromethyl, chloro, fluoro, methyl, methoxy and methanethio.

In accordance with other embodiments of the invention, one of R², R³ andR⁴ is H, another of R², R³ and R⁴ is Cl, and the third of R², R³ and R⁴is F, Cl or methoxy. In accordance with other embodiments of theinvention, one of R², R³ and R⁴ is H, another of R², R³ and R⁴ is F, andthe third of R², R³ and R⁴ is methoxy. In accordance with otherembodiments of the invention, one of R², R³ and R⁴ is H, another of R²,R³ and R⁴ is methoxy, and the third of R², R³ and R⁴ is methyl.

In accordance with some embodiments of the invention, B, together withR², R³ and R⁴, is selected from phenyl, 4-trifluoromethylphenyl,4-chlorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl,4-chloro-2-fluorophenyl, 2-fluoro-4-methoxyphenyl, pyridin-2-yl,5-chloropyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl,5-fluoropyridin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl,6-methylpyridazin-3-yl, 4-fluoro-2-methoxyphenyl,6-(trifluoromethyl)pyridin-3-yl, 2-(trifluoromethyl)pyrimidin-5-yl,5-(trifluoromethyl)pyrimidin-2-yl, 5-methylpyridin-2-yl,6-methylpyridin-3-yl, cyclohexyl, 4-chloro-2-methoxyphenyl,pyrimidin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-2-yl,4-methoxyphenyl, 4-methanethiophenyl and 4-methoxy-2-methylphenyl.

In accordance with some embodiments of the invention, at least one ofR⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁹ and R²⁰ is H. In other embodiments, atleast one of R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁹ and R²⁰ is optionallysubstituted alkyl, for example, methyl, ethyl, or hydroxymethyl.

In accordance with some embodiments of the invention, the compound isselected

In accordance with some embodiments of the invention, the compound is apharmaceutically acceptable salt thereof. In some embodiments, the saltis an HCl salt. There is also provided, in accordance with embodimentsof the invention, a pharmaceutical composition comprising a compound asdescribed herein, and a pharmaceutically acceptable carrier, excipientor diluent therefore.

There is also provided, in accordance with embodiments of the invention,a method of treating obesity, comprising administering to a patient inneed of obesity reduction an obesity-reducing effective amount of acompound as described herein.

There is also provided, in accordance with embodiments of the invention,a method of treating anxiety, comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundas described herein.

There is also provided, in accordance with embodiments of the invention,a method of treating depression, comprising administering to a patientin need of such treatment a therapeutically effective amount of acompound as described herein.

There is also provided, in accordance with embodiments of the invention,a method of treating non-alcoholic fatty liver disease, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound as described herein.

There is also provided, in accordance with embodiments of the invention,a method of treating a disease or condition which is susceptible totreatment with an MCH₁ receptor modulator, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundas described herein.

DEFINITIONS

Throughout this specification the terms and substituents retain theirdefinitions. Alkyl is intended to include linear, branched, or cyclichydrocarbon structures and combinations thereof. When not otherwiserestricted, the term refers to alkyl of 20 or fewer carbons. Lower alkylrefers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples oflower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Cycloalkyl is a subset of alkyl and includescyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examplesof cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl,adamantyl and the like.

C₁ to C₂₀ Hydrocarbon (e.g. C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀) includes alkyl,cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examplesinclude benzyl, phenethyl, cyclohexylmethyl, camphoryl andnaphthylethyl. The term “phenylene” refers to ortho, meta or pararesidues of the formulae:

Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbonatoms of a straight, branched, cyclic configuration and combinationsthereof attached to the parent structure through an oxygen. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like. Lower-alkoxy refers to groups containing oneto four carbons. For the purposes of the present patent applicationalkoxy also includes methylenedioxy and ethylenedioxy in which eachoxygen atom is bonded to the atom, chain or ring from which themethylenedioxy or ethylenedioxy group is pendant so as to form a ring.Thus, for example, phenyl substituted by alkoxy may be, for example,

Oxaalkyl refers to alkyl residues in which one or more carbons (andtheir associated hydrogens) have been replaced by oxygen. Examplesinclude methoxypropoxy, 3,6,9-trioxadecyl and the like. The termoxaalkyl is intended as it is understood in the art [see Naming andIndexing of Chemical Substances for Chemical Abstracts, published by theAmerican Chemical Society, ¶196, but without the restriction of¶127(a)], i.e. it refers to compounds in which the oxygen is bonded viaa single bond to its adjacent atoms (forming ether bonds). Similarly,thiaalkyl and azaalkyl refer to alkyl residues in which one or morecarbons have been replaced by sulfur or nitrogen, respectively. Examplesinclude ethylaminoethyl and methylthiopropyl.

Acyl refers to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of astraight, branched, cyclic configuration, saturated, unsaturated andaromatic and combinations thereof, attached to the parent structurethrough a carbonyl functionality. One or more carbons in the acylresidue may be replaced by nitrogen, oxygen or sulfur as long as thepoint of attachment to the parent remains at the carbonyl. Examplesinclude formyl, acetyl, propionyl, isobutyryl, t-butoxycarbonyl,benzoyl, benzyloxycarbonyl and the like. Lower-acyl refers to groupscontaining one to four carbons.

Aryl and heteroaryl refer to aromatic or heteroaromatic rings,respectively, as substituents. Heteroaryl contains one, two or threeheteroatoms selected from O, N, or S. Both refer to monocyclic 5- or6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-memberedaromatic or heteroaromatic rings and tricyclic 13- or 14-memberedaromatic or heteroaromatic rings. Aromatic 6, 7, 8, 9, 10, 11, 12, 13and 14-membered carbocyclic rings include, e.g., benzene, naphthalene,indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-memberedaromatic heterocyclic rings include, e.g., imidazole, pyridine, indole,thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline,isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples arebenzyl, phenethyl and the like.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in eachresidue are replaced with alkyl, halogen, haloalkyl, hydroxy,loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl),carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl,nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide,sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy,benzyloxy, or heteroaryloxy.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “prodrug” refers to a compound that is made more active invivo. Commonly the conversion of prodrug to drug occurs by enzymaticprocesses in the liver or blood of the mammal. Many of the compounds ofthe invention may be chemically modified without absorption into thesystemic circulation, and in those cases, activation in vivo may comeabout by chemical action (as in the acid-catalyzed cleavage in thestomach) or through the intermediacy of enzymes and microflora in thegastrointestinal GI tract.

In the characterization of some of the substituents, it is recited thatcertain substituents may combine to form rings. Unless stated otherwise,it is intended that such rings may exhibit various degrees ofunsaturation (from fully saturated to fully unsaturated), may includeheteroatoms and may be substituted with lower alkyl or alkoxy.

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine, iodine and chlorine include ³H, ¹⁴C, ³⁵S,¹⁸F, ³²P, ³³P, ¹²⁵I, and ³⁶Cl, respectively. Compounds that containthose radioisotopes and/or other radioisotopes of other atoms are withinthe scope of this invention. Radiolabeled compounds described herein andprodrugs thereof can generally be prepared by methods well known tothose skilled in the art. Conveniently, such radiolabeled compounds canbe prepared by carrying out the procedures disclosed in the Examples andSchemes by substituting a readily available radiolabeled reagent for anon-radiolabeled reagent.

The terms “methods of treating or preventing” mean amelioration,prevention or relief from the symptoms and/or effects associated withlipid disorders. The term “preventing” as used herein refers toadministering a medicament beforehand to forestall or obtund an acuteepisode or, in the case of a chronic condition to diminish thelikelihood or seriousness of the condition. The person of ordinary skillin the medical art (to which the present method claims are directed)recognizes that the term “prevent” is not an absolute term. In themedical art it is understood to refer to the prophylactic administrationof a drug to substantially diminish the likelihood or seriousness of acondition, and this is the sense intended in applicants' claims. As usedherein, reference to “treatment” of a patient is intended to includeprophylaxis.

Throughout this application, various references are referred to. Each ofthe patents, patent applications, patent publications, and referencesmentioned herein is hereby incorporated by reference in its entirety.

The term “mammal” is used in its dictionary sense. The term “mammal”includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats,and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits,guinea pigs, and primates, including humans.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Each chiral center may be defined, in terms ofabsolute stereochemistry, as (R)— or (S)—. The present invention ismeant to include all such possible isomers, as well as mixtures thereof,including racemic and optically pure forms. Optically active (R)— and(S)—, (−)- and (+)-, or (D)- and (L)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration; thus a carbon-carbon double bonddepicted arbitrarily herein as E may be Z, E, or a mixture of the two inany proportion. Likewise, all tautomeric forms are also intended to beincluded.

As used herein, and as would be understood by the person of skill in theart, the recitation of “a compound” is intended to include salts,solvates and inclusion complexes of that compound as well as anystereoisomeric form, or a mixture of any such forms of that compound inany ratio. Thus, in accordance with some embodiments of the invention, acompound as described herein, including in the contexts ofpharmaceutical compositions, methods of treatment, and compounds per se,is provided as the salt form. In accordance with some embodiments of theinvention, the salt is a hydrochloride salt.

The term “enantiomeric excess” is well known in the art and is definedfor a resolution of ab into a+b as

${ee}_{a} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} + {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}} \right) \times 100}$

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number from 0 to 100, zero being racemic and 100 beingpure, single enantiomer. A compound which in the past might have beencalled 98% optically pure is now more precisely described as 96% ee; inother words, a 90% ee reflects the presence of 95% of one enantiomer and5% of the other in the material in question.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference. Particularattention is drawn to the chapters entitled “Protection for the HydroxylGroup, Including 1,2- and 1,3-Diols” (pages 10-86).

The following abbreviations and terms have the indicated meaningsthroughout: Ac=acetyl; Bu=butyl; c-=cyclo; DIEA=N,N-diisopropylethylamine; TEA=triethylamine; HOAc=acetic acid; mesyl=methanesulfonyl;rt=room temperature; sat'd saturated; s-=secondary; t-=tertiary;TMS=trimethylsilyl; tosyl=p-toluenesulfonyl; TFA=trifluoroacetic acid;HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate. The abbreviations HPLC, THF, DCM and DMSO representhigh performance liquid chromatography, tetrahydrofuran, dichloromethaneand dimethylsulfoxide, respectively. The abbreviations Me, Et, Ph, Tf,Ts, Boc and Ms represent methyl, ethyl, phenyl,trifluoromethanesulfonyl, toluenesulfonyl, butyloxycarbonyl andmethanesulfonyl respectively. The term dppf refers to1,1′-Bis-(diphosphenylphosphino)ferrocene. A comprehensive list ofabbreviations utilized by organic chemists (i.e. persons of ordinaryskill in the art) appears in the first issue of each volume of theJournal of Organic Chemistry. The list, which is typically presented ina table entitled “Standard List of Abbreviations” is incorporated hereinby reference.

While it may be possible for the compounds of the invention to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. In accordance with an embodiment of thepresent invention there is provided a pharmaceutical compositioncomprising a compound of formula I or a pharmaceutically acceptable saltor solvate thereof, together with one or more pharmaceutically carriersthereof and optionally one or more other therapeutic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof. Furthermore, notwithstanding the statement aboveregarding the term “compound” including salts thereof as well, so thatindependent claims reciting “a compound” will be understood as referringto salts thereof as well, if in an independent claim reference is madeto a compound or a pharmaceutically acceptable salt thereof, it will beunderstood that claims which depend from that independent claim whichrefer to such a compound also include pharmaceutically acceptable saltsof the compound, even if explicit reference is not made to the salts inthe dependent claim.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy.Such methods include the step of bringing into association a compound offormula I or a pharmaceutically acceptable salt or solvate thereof(“active ingredient”) with the carrier, which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed or controlled releaseof the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceuticallyacceptable inert carrier”, and this expression is intended to includeone or more inert excipients, which include starches, polyols,granulating agents, microcrystalline cellulose, diluents, lubricants,binders, disintegrating agents, and the like. If desired, tablet dosagesof the disclosed compositions may be coated by standard aqueous ornonaqueous techniques, “Pharmaceutically acceptable carrier” alsoencompasses controlled release means.

Pharmaceutical compositions may also optionally include othertherapeutic ingredients, anti-caking agents, preservatives, sweeteningagents, colorants, flavors, desiccants, plasticizers, dyes, and thelike. Any such optional ingredient must be compatible with the compoundof formula I to insure the stability of the formulation. The compositionmay contain other additives as needed, including for example lactose,glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose,maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol,mannitol, myoinositol, and the like, and hydrates thereof, and aminoacids, for example alanine, glycine and betaine, and peptides andproteins, for example albumen.

Examples of excipients for use as the pharmaceutically acceptablecarriers and the pharmaceutically acceptable inert carriers and theaforementioned additional ingredients include, but are not limited tobinders, fillers, disintegrants, lubricants, anti-microbial agents, andcoating agents.

The dose range for adult humans is generally from 0.005 mg to 10 g/dayorally. Tablets or other forms of presentation provided in discreteunits may conveniently contain an amount of compound of formula I whichis effective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. Theprecise amount of compound administered to a patient will be theresponsibility of the attendant physician. However, the dose employedwill depend on a number of factors, including the age and sex of thepatient, the precise disorder being treated, and its severity. A dosageunit (e.g. an oral dosage unit) can include from, for example, 1 to 30mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of acompound described herein.

For additional information about pharmaceutical compositions and theirformulation, see, for example, Remington: The Science and Practice ofPharmacy, 20^(th) Edition, 2000.

The agents can be administered, e.g., by intravenous injection,intramuscular injection, subcutaneous injection, intraperitonealinjection, topical, sublingual, intraarticular (in the joints),intradermal, buccal, ophthalmic (including intraocular), intranasaly(including using a cannula), or by other routes. The agents can beadministered orally, e.g., as a tablet or cachet containing apredetermined amount of the active ingredient, gel, pellet, paste,syrup, bolus, electuary, slurry, capsule, powder, granules, as asolution or a suspension in an aqueous liquid or a non-aqueous liquid,as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion,via a micellar formulation (see, e.g. WO 97/11682) via a liposomalformulation (see, e.g., EP 736299, WO 99/59550 and WO 97/13500), viaformulations described in WO 03/094886 or in some other form. The agentscan also be administered transdermally (i.e. via reservoir-type ormatrix-type patches, microneedles, thermal poration, hypodermic needles,iontophoresis, electroporation, ultrasound or other forms ofsonophoresis, jet injection, or a combination of any of the precedingmethods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:115)).The agents can be administered locally, for example, at the site ofinjury to an injured blood vessel. The agents can be coated on a stent.The agents can be administered using high-velocity transdermal particleinjection techniques using the hydrogel particle formulation describedin U.S. 20020061336. Additional particle formulations are described inWO 00/45792, WO 00/53160, and WO 02/19989. An example of a transdermalformulation containing plaster and the absorption promoterdimethylisosorbide can be found in WO 89/04179. WO 96/11705 providesformulations suitable for transdermal administration.

The agents can be administered in the form a suppository or by othervaginal or rectal means. The agents can be administered in atransmembrane formulation as described in WO 90/07923. The agents can beadministered non-invasively via the dehydrated particles described inU.S. Pat. No. 6,485,706. The agent can be administered in anenteric-coated drug formulation as described in WO 02/49621. The agentscan be administered intranasaly using the formulation described in U.S.Pat. No. 5,179,079. Formulations suitable for parenteral injection aredescribed in WO 00/62759. The agents can be administered using thecasein formulation described in U.S. 20030206939 and WO 00/06108. Theagents can be administered using the particulate formulations describedin U.S. 20020034536.

The agents, alone or in combination with other suitable components, canbe administered by pulmonary route utilizing several techniquesincluding but not limited to intratracheal instillation (delivery ofsolution into the lungs by syringe), intratracheal delivery ofliposomes, insufflation (administration of powder formulation by syringeor any other similar device into the lungs) and aerosol inhalation.Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers(MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasalapplications. Aerosol formulations are stable dispersions or suspensionsof solid material and liquid droplets in a gaseous medium and can beplaced into pressurized acceptable propellants, such ashydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixturethereof), dichlorodifluoromethane (or other chlorofluorocarbonpropellants such as a mixture of Propellants 11, 12, and/or 114),propane, nitrogen, and the like. Pulmonary formulations may includepermeation enhancers such as fatty acids, and saccharides, chelatingagents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g.,glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g.,benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5%but possibly up to 20%, by weight). Ethanol is commonly included inaerosol compositions as it can improve the function of the meteringvalve and in some cases also improve the stability of the dispersion.

Pulmonary formulations may also include surfactants which include butare not limited to bile salts and those described in U.S. Pat. No.6,524,557 and references therein. The surfactants described in U.S. Pat.No. 6,524,557, e.g., a C₈-C₁₆ fatty acid salt, a bile salt, aphospholipid, or alkyl saccharide are advantageous in that some of themalso reportedly enhance absorption of the compound in the formulation.

Also suitable in the invention are dry powder formulations comprising atherapeutically effective amount of active compound blended with anappropriate carrier and adapted for use in connection with a dry-powderinhaler. Absorption enhancers that can be added to dry powderformulations of the present invention include those described in U.S.Pat. No. 6,632,456. WO 02/080884 describes new methods for the surfacemodification of powders. Aerosol formulations may include U.S. Pat. No.5,230,884, U.S. Pat. No. 5,292,499, WO 017/8694, WO 01/78696, U.S.2003019437, U.S. 20030165436, and WO 96/40089 (which includes vegetableoil). Sustained release formulations suitable for inhalation aredescribed in U.S. 20010036481A1, 20030232019A1, and U.S. 20040018243A1as well as in WO 01/13891, WO 02/067902, WO 03/072080, and WO 03/079885.

Pulmonary formulations containing microparticles are described in WO03/015750, U.S. 20030008013, and WO 00/00176. Pulmonary formulationscontaining stable glassy state powder are described in U.S. 20020141945and U.S. Pat. No. 6,309,671. Other aerosol formulations are described inEP 1338272A1 WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No.6,436,367, WO 91/04011, and U.S. Pat. No. 6,294,153 and U.S. Pat. No.6,290,987 describes a liposomal based formulation that can beadministered via aerosol or other means.

Powder formulations for inhalation are described in U.S. 20030053960 andWO 01/60341. The agents can be administered intranasally as described inU.S. 20010038824. Solutions of medicament in buffered saline and similarvehicles are commonly employed to generate an aerosol in a nebulizer.Simple nebulizers operate on Bernoulli's principle and employ a streamof air or oxygen to generate the spray particles. More complexnebulizers employ ultrasound to create the spray particles. Both typesare well known in the art and are described in standard textbooks ofpharmacy such as Sprowls' American Pharmacy and Remington's The Scienceand Practice of Pharmacy.

Other devices for generating aerosols employ compressed gases, usuallyhydrofluorocarbons and chlorofluorocarbons, which are mixed with themedicament and any necessary excipients in a pressurized container,these devices are likewise described in standard textbooks such asSprowls and Remington.

The agent can be incorporated into a liposome to improve half-life. Theagent can also be conjugated to polyethylene glycol (PEG) chains.Methods for pegylation and additional formulations containingPEG-conjugates (i.e. PEG-based hydrogels, PEG modified liposomes) can befound in Harris and Chess, Nature Reviews Drug Discovery 2:214-221 andthe references therein. The agent can be administered via ananocochleate or cochleate delivery vehicle (BioDelivery SciencesInternational). The agents can be delivered transmucosally (i.e. acrossa mucosal surface such as the vagina, eye or nose) using formulationssuch as that described in U.S. Pat. No. 5,204,108. The agents can beformulated in microcapsules as described in WO 88/01165. The agent canbe administered intra-orally using the formulations described in U.S.20020055496, WO 00/47203, and U.S. Pat. No. 6,495,120. The agent can bedelivered using nanoemulsion formulations described in WO 01/91728A2.

TABLE 1 lists compounds representative of embodiments of the invention.In general, the compounds of the present invention may be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants that are inthemselves known, but are not mentioned here.

Processes for obtaining the compounds of the invention are presentedbelow. Other compounds of the invention may be prepared in analogousfashion to those whose synthesis is exemplified herein. The proceduresbelow illustrate such methods. Furthermore, although the synthesesdepicted herein may result in the preparation of enantiomers having aparticular stereochemistry, included within the scope of the presentinvention are compounds of formula I in any stereoisomeric form, andpreparation of compounds of formula I in stereoisomeric forms other thanthose depicted herein would be obvious to one of ordinary skill in thechemical arts based on the procedures presented herein.

Synthetic Methods

Compounds of formula 3 (wherein R¹⁴ is H or halogen; R¹ is H; R⁵ is aprotecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; R⁸,R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from H oroptionally substituted alkyl) can be prepared from 3- or 4-bromophenylhydrazine 1 (or a salt thereof) and piperidinone 2 under heatedacidic conditions. Optional N5-alkylation or N5-protection of compound 3can provide compounds of formula 3 wherein R¹ is alkyl or a protectinggroup such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl. Optional removal of N2-protecting group R⁵ andreductive amination, alkylation or acylation can provide compounds offormula 3 wherein R⁵ is alkyl or acyl.

Compounds of formula I (wherein R¹⁴ is H or halogen) can be treated withcompounds of formula 4 (wherein R¹² and R¹³ are each independentlyselected from H or optionally substituted alkyl and R¹⁶ is alkyl) and aLewis acid such as ZnCl₂ under heated conditions to give compounds offormula 5. Treatment of compounds of formula 5 with ethyl glyoxylateunder heated acidic conditions can provide compounds of formula 6wherein R¹⁰ and R¹¹ are H. Alternatively, compounds of formula 5 can betreated with a ketone under heated acidic conditions to providecompounds of formula 6 wherein R¹⁰ and R¹¹ are optionally substitutedalkyl. Compounds of formula 5 also can be treated with an acid chlorideunder basic conditions, followed by heating with POCl₃ and finally bytreatment with a reducing agent such as NaBH₄ to provide compounds offormula 6 wherein R¹⁰ is H and R¹¹ is optionally substituted alkyl.Protection of the N²-position on the tetrahydrocarboline ring canprovide compounds of formula 7 (wherein R⁵ is a protecting group such astert-butoxycarbonyl or benzyloxycarbonyl). Protection of the N9-positionon the tetrahydrocarboline ring can provide compounds of formula 8(wherein R¹ is a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl). Alternatively, treatment ofcompound 7 with a base such as sodium hydride and an alkylating agentcan provide compounds of formula 8 wherein R¹ is optionally substitutedalkyl. Optional removal of N2-protecting group R⁵ and reductiveamination, alkylation or acylation can provide compounds of formula 8wherein R⁵ is alkyl or acyl.

Compounds of formula 12 (wherein B is aryl or heteroaryl; R², R³, R⁴ areeach independently selected from H, —O-alkyl, S-alkyl, alkyl, halo,—CF₃, and —CN; and Y is CH) can be prepared by treating compounds offormula 9 (wherein X¹ is chlorine, bromine or iodine and Y is CH) withcompounds of formula 10 (wherein B is aryl or heteroaryl; R², R³, R⁴ areeach independently selected from H, —O-alkyl, alkyl, halo, —CF₃, and—CN; Z¹ is B(OH)₂, B(OR¹⁷)₂, SnR¹⁷ ₃ or the like and R¹⁷ is alkyl), acatalyst such as palladium(0), and a base such as potassium carbonate togive compounds of formula II, wherein L is a direct bond. Alternatively,in the case where Z¹ is —CH₂OH and B is aryl, heteroaryl or cycloalkyl,compounds of formula 10 can be treated with a base such as sodiumhydride and compounds of formula 9 under heated conditions to givecompounds of formula II, wherein L is —CH₂O—. In turn, compounds offormula II can be treated with acetic anhydride under heated conditionsfollowed by methanol and water or methanol and sodium hydroxide underambient to heated conditions to provide compounds of formula 12, whereinL is —CH₂O— or a direct bond.

Alternatively, compounds of formula 12 (wherein B is aryl or heteroaryl;R², R³, R⁴ are each independently selected from H, —O-alkyl, S-alkyl,alkyl, halo, —CF₃, and —CN; and Y is CH) can be prepared by treatingcompounds of formula 13 (wherein X is chlorine, bromine or iodine and Yis CH) with compounds of formula 10 (wherein Z¹ is —CH═CH—B(OR¹⁷)₂,B(OR¹⁷)₂, SnR¹⁷ ₃ or the like and R¹⁷ is H or alkyl), a catalyst such aspalladium(0), and a base such as potassium carbonate to give compoundsof formula 14, wherein L is —CH═CH— or a direct bond, in accordance withZ¹. In the case where L is —CH═CH—, compounds of formula 14 can betreated with palladium on carbon under an atmosphere of hydrogen to givecompounds of formula 14, wherein L is —CH₂CH₂—. Alternatively, in thecase where Z¹ is —CH₂OH, compounds of formula 10 can be treated withcompounds of formula 13, a catalyst such as copper iodide, a ligand suchas 3,4,7,8-tetramethylphenanthroline and a base such as cesium carbonateunder heated conditions to give compounds of formula 14, wherein L is—CH₂O—. In turn, when L is —CH═CH—, —CH₂CH₂—, —CH₂O— or a direct bond,compounds of formula 14 can be heated under acid conditions to providecompounds of formula 12, wherein L is —CH═CH—, —CH₂CH₂—, —CH₂O— or adirect bond, respectively.

Alternatively, compounds of formula 12 (wherein B is aryl or heteroaryl;R², R³, R⁴ are each independently selected from H, —O-alkyl, S-alkyl,alkyl, halo, —CF₃, and —CN; and Y is N) can be prepared from compoundsof formula 15 (wherein Y is N and R¹⁸ is a protecting group such astetrahydropyran-2-yl). The hydroxyl group on compound 15 can beconverted to an appropriate activating group to give compounds offormula 16. In the case where Z² is triflate, compounds of formula 15can be treated with trifluoromethylsulfonic anhydride or N-phenyltrifluoromethanesulfonamide and a base such as triethylamine, pyridineor lithium bis(trimethylsilyl)amide under cooled conditions to givecompounds of formula 16. Treatment of compounds of formula 16 withcompounds of formula 10 (wherein B is aryl or heteroaryl; R², R³, R⁴ areeach independently selected from H, —O-alkyl, S-alkyl, alkyl, halo,—CF₃, and —CN; Z¹=CH═CH—B(OR¹⁷)₂, B(OH)₂, B(OR¹⁷)₂, SnR¹⁷ ₃ or the like,and R¹⁷=alkyl), a catalyst such as palladium(0), and a base such aspotassium carbonate under heated conditions can provide compounds offormula 17, wherein L is —CH═CH— or a direct bond. Removal of theprotecting group R¹⁸ on compound 17 can provide compounds of formula 12.

Compounds of formula 18 (wherein B is aryl, heteroaryl or cycloalkyl;R², R³, R⁴ are each independently selected from H, —O-alkyl, —S-alkyl,alkyl, halo, —CF₃, and —CN; L is —CH₂—O—, —CH═CH—, —CH₂CH₂—, or a bond;Y is CH or N; R¹⁴ is H or halogen; R⁵ is alkyl, acyl or a protectinggroup such as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or aprotecting group such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl; and R⁸, R⁹, R¹⁰, R¹¹, and R¹³ are each independentlyselected from H or optionally substituted alkyl) can be prepared bytreating compounds of formula 3 (wherein R⁵ is alkyl, acyl or aprotecting group such as tert-butoxycarbonyl or benzyloxycarbonyl and R¹is alkyl or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl) under heated conditions with acatalyst such as copper iodide, a ligand such astrans-1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such aspotassium carbonate, cesium carbonate or potassium phosphate andcompounds of formula 12 (wherein B is aryl, heteroaryl or cycloalkyl;R², R³, R⁴ are each independently selected from H, —O-alkyl, —S-alkyl,alkyl, halo, —CF₃, and —CN; L is —CH₂—O—, —CH═CH—, —CH₂CH₂—, or a bond;and Y is CH or N). Removal of the N2-protecting group R⁵ followed byreductive amination or alkylation can provide compounds of formula 18,wherein R⁵ is an optionally substituted alkyl group.

Alternatively, following deprotection, N2 can be acylated to givecompounds of formula 18 wherein R⁵ is —C(═O)—R⁶ or —C(═O)—O—R⁷, and R⁶and R⁷ are each optionally substituted alkyl or optionally substitutedheterocycle. Additionally, in the case where R¹ is a protecting group,the protecting group can be removed to give compounds of formula 18wherein R¹ is H.

Alternatively, following removal of the R¹ protecting group, N5 can bealkylated to give compounds of formula 18 wherein R⁵ is an optionallysubstituted alkyl.

Compounds of formula 19 (wherein B is aryl, heteroaryl or cycloalkyl;R², R³, R⁴ are each independently selected from H, —O-alkyl, —S-alkyl,alkyl, halo, —CF₃, and —CN; L is —CH₂—O—, —CH═CH—, —CH₂CH₂—, or a bond;Y is CH or N; R¹⁴ is H or halogen; R⁵ is alkyl, acyl or a protectinggroup such as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or aprotecting group such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl; and R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are eachindependently selected from H or optionally substituted alkyl) can beprepared by treating compounds of formula 3 (wherein R⁵ is alkyl, acylor a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyland R¹ is alkyl or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl) under heated conditions with acatalyst such as copper iodide, a ligand such astrans-1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such aspotassium carbonate, cesium carbonate or potassium phosphate andcompounds of formula 12 (wherein B is aryl, heteroaryl or cycloalkyl;R², R³, R⁴ are each independently selected from H, —O-alkyl, —S-alkyl,alkyl, halo, —CF₃, and —CN; L is —CH₂—O—, —CH═CH—, —CH₂CH₂—, or a bond;and Y is CH or N). Removal of the N2-protecting group R⁵ followed byreductive amination or alkylation can provide compounds of formula 18,wherein R⁵ is an optionally substituted alkyl group.

Alternatively, following deprotection, N2 can be acylated to givecompounds of formula 18 wherein R⁵ is —C(═O)—R⁶ or —C(═O)—O—R⁷, and R⁶and R⁷ are each optionally substituted alkyl or optionally substitutedheterocycle. Additionally, in the case where R¹ is a protecting group,the protecting group can be removed to give compounds of formula 18wherein R¹ is H.

Alternatively, following removal of the R¹ protecting group, N5 can bealkylated to give compounds of formula 18 wherein R⁵ is an optionallysubstituted alkyl.

Compounds of formula 20 (wherein Y is CH or N; R¹⁴ is H or halogen; R⁵is alkyl, acyl or a protecting group such as tert-butoxycarbonyl orbenzyloxycarbonyl; R¹ is alkyl or a protecting group such astert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; and R⁸, R⁹,R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from H oroptionally substituted alkyl) can be treated with hydrogen and acatalyst such as palladium on carbon to provide compounds of formula 21.The hydroxyl group on compounds of formula 21 can be converted to anappropriate activating group to give compounds of formula 22. In thecase where Z² is triflate, compounds of formula 21 can be treated withtrifluoromethylsulfonic anhydride or N-phenyltrifluoromethanesulfonamide and a base such as pyridine or lithiumbis(trimethylsilyl)amide under cooled conditions to give compounds offormula 22. Treatment of compounds of formula 22 with compounds offormula 10 (wherein B is aryl or heteroaryl; R², R³, R⁴ are eachindependently selected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF₃,and —CN; Z¹=—CH═CH—B(OR¹⁷)₂, B(OH)₂, B(OR¹⁷)₂, SnR¹⁷ ₃ or the like andR¹⁷=alkyl), a catalyst such as palladium(0), and a base such aspotassium carbonate under heated conditions can provide compounds offormula 18, wherein L is —CH═CH— or a direct bond. In the case where Lis —CH═CH—, compounds of formula 18 can be treated with palladium oncarbon under an atmosphere of hydrogen to give compounds of formula 18,where L is —CH₂CH₂—.

Compounds of formula 23 (wherein Y is CH or N; R¹⁴ is H or halogen; R⁵is alkyl, acyl or a protecting group such as tert-butoxycarbonyl orbenzyloxycarbonyl; R¹ is alkyl or a protecting group such astert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl; and R⁸, R⁹,R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from H oroptionally substituted alkyl) can be treated with hydrogen and acatalyst such as palladium on carbon to provide compounds of formula 24.The hydroxyl group on compounds of formula 24 can be converted to anappropriate activating group to give compounds of formula 25. In thecase where Z² is triflate, compounds of formula 24 can be treated withtrifluoromethylsulfonic anhydride or N-phenyltrifluoromethanesulfonamide and a base such as pyridine or lithiumbis(trimethylsilyl)amide under cooled conditions to give compounds offormula 25.

Treatment of compounds of formula 25 with compounds of formula 10(wherein B is aryl or heteroaryl; R², R³, R⁴ are each independentlyselected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF₃, and —CN;Z¹=—CH═CH—B(OR¹⁷)₂, B(OH)₂, B(OR¹⁷)₂, SnR¹⁷ ₃ or the like andR¹⁷=alkyl), a catalyst such as palladium(0), and a base such aspotassium carbonate under heated conditions can provide compounds offormula 19, wherein L is —CH═CH— or a direct bond.

In the case where L is —CH═CH—, compounds of formula 18 can be treatedwith palladium on carbon under an atmosphere of hydrogen to givecompounds of formula 18, where L is —CH₂CH₂—.

Compounds of formula 26 (wherein B is aryl or heteroaryl; R², R³, R⁴ areeach independently selected from H, —O-alkyl, —S-alkyl, alkyl, halo,—CF₃, and —CN; L is —CH₂—O—, —CH═CH—, —CH₂CH₂—, or a bond; G is—CR¹²R¹³—NH— or —NH—CR¹²R¹³—; R¹ is alkyl; and R⁸, R⁹, R¹⁰, R¹¹, R¹² andR¹³ are each independently selected from H or optionally substitutedalkyl) can be treated under halogenation conditions such as2-bromopropane under heated conditions to provide compounds of formula27 wherein R¹⁵ is a halogen such as bromine.

EXAMPLES

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on Bruker spectrometers at 300, 400 or 500 MHz. Spectraare given in ppm (δ) and coupling constants, J, are reported in Hertz.Tetramethylsilane (TMS) was used as an internal standard. Mass spectrawere collected using either a Finnigan LCQ Duo LCMS ion trapelectrospray ionization (ESI) or a mass Varian 1200L single quadrapolemass spectrometer (ESI). High performace liquid chromatograph (HPLC)analyses were obtained using a Luna C18(2) column (250×4.6 mm,Phenomenex) or a Gemini C18 column (250×4.6 mm, Phenomenex) with UVdetection at 254 nm or 223 nm using a standard solvent gradient program(Method A or Method B).

Method A: Time Flow (min) (mL/min) % A % B 0.0 1.0 90.0 10.0 20 1.0 10.090.0 25 1.0 10.0 90.0 A = Water with 0.025% Trifluoroacetic Acid B =Acetonitrile with 0.025% Trifluoroacetic Acid

Method B: Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0 2.0 25 1.0 10.090.0 30 1.0 10.0 90.0 A = Water with 0.025% Trifluoroacetic Acid B =Acetonitrile with 0.025% Trifluoroacetic Acid

Example 1 Preparation of4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

3-Bromophenylhydrazine (40.0 g, 0.179 mol) and N-Boc-4-oxo-piperidine(35.4 g, 0.179 mol) were dissolved in ethanol (368 mL), and conc. HCl(72 mL) was added. The reaction mixture was then heated to reflux for 18h, concentrated and basified using 10% NH₄OH in methanol (10%, 100 mL).The solvent was removed, and the residue was suspended in CH₂Cl₂ (1.2L). Boc₂O (39.2 g, 0.179 mol) followed by DMAP (195 mg, 1.6 mmol) andtriethylamine (46.4 mL, 0.358 mol) were then added, and the reactionprogressed at room temperature for 18 h. The mixture was washed with 0.5N HCl, and the organic phase was removed, dried over Na₂SO₄, filteredand concentrated to dryness. The resulting mixture of regioisomers waspurified by flash column chromatography (silica gel, hexanes/EtOAc,100:0 to 80:20 to 50:50 then 25:75) to give the more polar titlecompound (26.2 g, 42%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.16(br s, 1H), 7.42 (s, 1H), 7.28 (d, J=8.1 Hz, 1H, partially masked bysolvent), 7.18 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 3.80 (t, J=5.5 Hz, 2H),2.79 (t, J=5.6 Hz, 2H), 1.51 (s, 9H).

b) tert-Butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Sodium hydride (60% weight dispersion in mineral oil, 4.19 g, 0.105 mol)was added portionwise to a solution of tert-butyl7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (23.6 g,0.07 mol) in DMF (300 mL) at room temperature under N₂. After 1 h,methyl iodide (14.8 g, 6.47 mL, 0.105 mol) was added, and the reactionwas allowed to proceed for an additional 2 h. The mixture was quenchedwith H₂O, upon which a solid precipitated out of solution. Thesuspension was therefore diluted to 2 L with H₂O and filtered. Thesolids were washed thoroughly with water, then dissolved in CH₂Cl₂,dried over Na₂SO₄, filtered and concentrated to dryness. This providedthe title compound (22.4 g, 91%) as a yellow solid: ¹H NMR (300 MHz,CDCl₃) δ 7.41 (s, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H),4.60 (s, 2H), 3.81 (br t, 2H), 3.58 (s, 3H), 2.77 (t, J=5.4 Hz, 2H),1.50 (s, 9H).

c) tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

tert-Butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(7.0 g, 19 mmol), 4-benzyloxypyridone (3.85 g, 19.2 mmol), K₂CO₃ (2.91g, 21.1 mmol) and 8-hydroxyquinoline (418 mg, 2.88 mmol) were suspendedin DMSO (50 mL) and the air removed under vacuum for 15 min. The systemwas then flushed with N₂. This process was repeated and then copperiodide (547 mg, 2.88 mmol) was added. The evacuation/N₂ flushing processwas repeated twice more, and the reaction mixture was heated to 100-120°C. for 18 h. The mixture was cooled, partitioned between EtOAc and sat.NH₄Cl and the organic phase removed, dried over Na₂SO₄, filtered andconcentrated to dryness. Purification by flash column chromatography(silica gel, CH₂Cl₂/MeOH, 100:0 to 98:2 to 95:5 to 92:8 then 90:10) gavethe title compound (4.71 g, 51%) as a yellow solid: ¹H NMR (300 MHz,CDCl₃) δ 7.50 (d, J=8.2 Hz, 1H), 7.43-7.35 (m, 5H), 7.32-7.29 (m, 2H),7.01 (d, J=7.9 Hz, 1H), 6.10-6.03 (m, 2H), 5.06 (s, 2H), 4.64 (s, 2H),3.89 (br t, 2H), 3.63 (s, 3H), 2.82 (br t, 2H), 1.50 (s, 9H).

d)4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(12.0 g, 24.7 mmol) was dissolved in MeOH (100 mL), and 2 N HCl in Et₂O(300 mL) was added. The reaction was allowed to proceed for 18 h. Themixture was concentrated, and the residue was partitioned between CH₂Cl₂and sat. Na₂CO₃ solution. The organic phase was removed, and the aqueousphase was back extracted with CH₂Cl₂. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated to dryness providing thefree base of the title compound (8.1 g, 85%) as a yellow solid. Aportion of the free base was converted to the HCl salt for biologicaltesting. Free base: ¹H NMR (500 MHz, CDCl₃) δ 7.47-7.34 (m, 6H),7.32-7.28 (m, 2H), 6.98 (d, J=7.1 Hz, 1H), 6.07 (d, J=2.6 Hz, 1H), 6.04(dd, J=7.5, 2.6 Hz, 1H), 5.05 (s, 2H), 4.15 (s, 2H), 3.61 (s, 3H), 3.34(br s, 2H), 2.78 (br s, 2H). HCl salt: melting point (mp) 296-302° C.;¹H NMR (500 MHz, CD₃OD) δ 7.61-7.57 (2×d, 2H), 7.47-7.46 (m, 3H),7.43-7.40 (m, 2H), 7.37-7.34 (m, 1H), 7.05 (dd, J=8.3, 1.7 Hz, 1H), 6.33(dd, J=7.5, 2.7 Hz, 1H), 6.16 (d, J=2.6 Hz, 1H), 5.19 (s, 2H), 4.57 (s,2H), 3.73 (s, 3H), 3.67 (t, J=6.2 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESIMS m/z 386 [M+H]⁺; HPLC (Method A) 95.7% (AUC), t_(R)=13.6 min.

Example 2 Preparation of4-(Benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(8.1 g, 21.0 mmol) and 37% aqueous formaldehyde (2.56 mL, 31.5 mmol)were dissolved in MeOH (200 mL) and stirred at room temperature for 2 h.Sodium triacetoxyborohydride (8.9 g, 42.0 mmol) was then added, and thereaction was stirred at room temperature for an additional 1 h. Themixture was concentrated, and the residue was partitioned between CH₂Cl₂and sat. Na₂CO₃ solution. The organic phase was removed and the aqueousphase was back extracted with CH₂Cl₂. The combined organics were driedover Na₂SO₄, filtered and concentrated to dryness. Purification bycolumn chromatography (120 g ISCO column eluting with methylene chlorideand a methanol/ammonia mixture (10:1); gradient 100% methylene chlorideto 85% methylene chloride over 60 min) provided the free base of thetitle compound. This was converted to the HCl salt using 2 N HCl in Et₂Oproviding the title compound (5.57 g, 61%) as a yellow solid: mp268-274° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.57 (dd, J=7.6, 1.7 Hz, 2H),7.47-7.46 (m, 3H) 7.43-7.34 (m, 3H), 7.06 (dd, J=8.4, 1.9 Hz, 1H), 6.29(dd, J=7.6, 2.7 Hz, 1H), 6.13 (d, J=2.6 Hz, 1H), 5.18 (s, 2H), 4.75 (d,J=14.3 Hz, 1H), 4.38 (d, J=14.2 Hz, 1H), 3.90 (m, 1H), 3.73 (s, 3H),3.64-3.58 (m, 1H), 3.29-3.26 (m, 2H, partially masked by solvent), 3.13(s, 3H); ESI MS m/z 400 [M+H]⁺; HPLC (Method B) 97.4% (AUC), t_(R)=14.7min.

Example 3 Preparation of4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride

4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(75 mg, 0.16 mmol), 2-iodoethanol (17 μL, 36 mg, 0.21 mmol) andtriethylamine (105 μL, 0.82 mmol) were dissolved in MeCN (2 mL) andheated to reflux for 3 h. The mixture was then concentrated and purifiedby flash column chromatography (4 g ISCO column eluting with methylenechloride and a methanol/ammonia mixture (10:1); gradient 100% methylenechloride to 85% methylene chloride over 30 min) providing the free base.This was converted to the HCl salt (2 N HCl/Et₂O) providing the titlecompound (22 mg, 27%) as a yellow solid: mp 162-168° C.; ¹H NMR (500MHz, CD₃OD) δ 7.63 (dd, J=7.6, 2.0 Hz, 2H), 7.51-7.50 (m, 3H) 7.46-7.43(m, 2H), 7.41-7.38 (m, 1H), 7.09 (dd, J=8.3, 1.7 Hz, 1H), 6.36 (dd,J=7.6, 2.7 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.82 (d, 1H,partially masked by solvent), 4.520 (d, J=14.3 Hz, 1H), 4.06-4.02 (m,3H), 3.77 (s, 3H), 3.70-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.33-3.31 (m,2H, partially masked by solvent); ESI MS m/z 430 [M+H]⁺; HPLC (Method B)95.1% (AUC), t_(R)=12.4 min.

Example 4 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride a)4-(Benzyloxy)-1-(2-(2-chloroacetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(75 mg, 0.16 mmol) was dissolved in a mixture of CH₂Cl₂ (1 mL) and sat.NaHCO₃ solution (1 mL) and chloroacetyl chloride (28 mg, 0.25 mmol) wasadded. The reaction mixture was vigorously stirred for 1 h then thephases were separated. The aqueous phase was extracted with CH₂Cl₂ andthe combined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness providing the title compound (74 mg, 97%) as abeige solid which was a mixture of rotamers: ESI MS m/z 462 [M+H]⁺.

b)4-(Benzyloxy)-1-(5-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

4-(Benzyloxy)-1-(2-(2-chloroacetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(70 mg, 0.15 mmol) was dissolved in MeCN (0.5 mL) and pyrrolidine (54mg, 0.76 mmol) was added. The reaction mixture was refluxed for 2 h,concentrated and the residue purified by preparative HPLC. The fractionswere concentrated, and the residue was converted to the free base bypartitioning between CH₂Cl₂ and sat. Na₂CO₃ solution. The organic phasewas removed, and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness. Conversion to the HCl salt (2 N HCl/Et₂O)provided the title compound (74 mg, 97%) as a beige solid: ¹H NMR (500MHz, CD₃OD) δ 7.62 (dd, J=7.7, 1.9 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H)7.46-7.44 (m, 2H), 7.41-7.35 (m, 4H), 7.06 (dd, J=8.0, 1.7 Hz, 1H), 6.36(d, J=7.6 Hz, 1H), 6.18 (s, 1H), 5.25 (s, 2H), 4.90 (m, 1H, masked bysolvent), 4.82 (s, 1H), 4.53 (d, J=14.2 Hz, 2H), 4.09 (t, J=6.5 Hz, 1H),3.91 (t, J=6.4 Hz, 1H), 3.89-3.86 (m, 2H), 3.77 (s, 3H), 3.20-3.18 (m,2H), 3.05-3.03 (m, 1H), 2.99-2.97 (m, 1H), 2.12-2.10 (m, 2H), 2.08-2.05(m, 2H); ESI MS m/z 497 [M+H]⁺; HPLC (Method B) 95.0% (AUC), t_(R)=13.1min.

Example 5 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride

4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(75 mg, 0.16 mmol) and triethylamine (105 μL, 0.753 mmol) were dissolvedin MeCN (2 mL) and 1,1,1-trifluoro-2-bromoethane (32 mg, 0.20 mmol) wasadded. The reaction mixture was heated to reflux for 4 h, but noreaction occurred. The mixture was concentrated, DMF (2 mL) and NaI (5mg) were added, and the reaction mixture was heated to reflux. Again, noreaction occurred. 1,1,1-trifluoroethyl triflate (76 mg, 0.328 mmol) wasthen added, and the mixture was heated to reflux. After 1.5 h, themixture was concentrated and purified by flash column chromatography (4g ISCO column eluting with methylene chloride and a methanol/ammoniamixture (10:1); gradient 100% methylene chloride to 85% methylenechloride over 30 min). Further purification by preparative HPLC,followed by conversion to the HCl salt (2 N HCl/Et₂O) provided the titlecompound (6 mg, 7%) as a white solid: ¹H NMR (300 MHz, CD₃OD) δ 7.48 (d,J=7.5 Hz, 1H), 7.40-7.24 (m, 7H), 6.87 (dd, J=8.3, 1.9 Hz, 1H), 6.19(dd, J=7.6, 2.7 Hz, 1H), 6.03 (d, J=2.7 Hz, 1H), 5.08 (s, 2H), 3.96 (s,2H), 3.58 (s, 3H), 3.37 (q, J=9.7 Hz, 2H), 3.15-3.14 (m, 2H, partiallymasked by solvent), 2.87 (t, J=5.5 Hz, 2H); ESI MS m/z 468 [M+H]⁺; HPLC(Method B) 98.9% (AUC), t_(R)=17.3 min.

Example 6 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride

4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(63 mg, 0.14 mmol) and K₂CO₃ (97 mg, 0.70 mmol) were suspended in DMF (1mL) and 1,1,1-trifluoro-3-bromopropane (50 mg, 0.28 mmol) was added. Thereaction mixture was heated to 80° C. for 18 h, cooled and partitionedbetween ethyl acetate and water. The aqueous phase was removed and theorganic phase washed with 5% LiCl (5×), dried over Na₂SO₄, filtered andconcentrated to dryness. Purification by flash column chromatography (4g ISCO column eluting with methylene chloride and a methanol/ammoniamixture (10:1); gradient 100% methylene chloride to 85% methylenechloride over 30 min) followed by conversion to the HCl salt (2 NHCl/Et₂O) provided the title compound (12 mg, 16%) as a yellow solid: ¹HNMR (500 MHz, CD₃OD) δ 7.66 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H),7.52-7.51 (m, 3H), 7.48-7.45 (m, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.11 (dd,J=8.3, 1.7 Hz, 1H), 6.36 (dd, J=7.6, 2.7 Hz, 1H), 6.19 (d, J=2.7 Hz,1H), 5.24 (s, 2H), 4.96 (m, 6H, masked by solvent), 3.79-3.74 (m, 5H),3.03-3.02 (m, 2H); ESI MS m/z 482 [M+H]⁺; HPLC (Method B) 95.6% (AUC),t_(R)=14.3 min.

Example 7 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-onedihydrochloride a) tert-Butyl5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

The compound was prepared from tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(250 mg, 0.701 mmol) and4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-one (142 mg, 0.526 mmol)according to the procedure in Example 1 (step c). Purification by flashcolumn chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to50:50 to 25:75 then 0:100) provided the title compound (73 mg, 19%) as asolid, that contained an impurity: ESI MS m/z 554 [M+H]⁺.

b)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(73 mg, 0.13 mmol) was dissolved in MeOH (0.5 mL) and 2 N HCl in Et₂O (3mL) was added. The reaction was allowed to proceed for 3 h. The mixturewas concentrated and purified by preparative HPLC. Converion to the HClsalt (2 NHCl/Et₂O) provided the title compound (26 mg, 38%) as a yellowsolid: mp 311-315° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.77 (d, J=8.3 Hz, 2H),7.71 (d, J=8.2 Hz, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H),7.50 (s, 1H), 7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.38 (dd, J=7.6, 2.7 Hz,1H), 6.17 (d, J=2.7 Hz, 1H), 5.33 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H),3.71 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.1 Hz, 2H); ESI MS m/z 454 [M+H]⁺;HPLC (Method B)>99% (AUC), t_(R)=14.2 min.

Example 8 Preparation of4-(4-Chlorobenzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

The compound was prepared from tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.548 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (129 mg,0.548 mmol) according to the procedure in Example 1 (step c).Purification by flash column chromatography (silica gel, hexanes/EtOAc,100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound(143 mg, 50%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.51 (d,J=8.0 Hz, 1H), 7.43-7.29 (m, 6H), 7.01 (d, J=7.9 Hz, 1H), 6.05-6.02 (m,2H), 5.02 (s, 2H), 4.64 (br s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.82(br s, 2H), 1.50 (s, 9H).

b)4-(4-Chlorobenzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl-7-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(143 mg, 0.275 mmol) was dissolved in MeOH (1 mL) and 2 N HCl in Et₂O (5mL) was added. The reaction was allowed to proceed for 3 h. Theresulting precipitate was collected by filtration and washed with Et₂Oto provide the title compound (95 mg, 71%) as a yellow solid: mp305-310° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (br s, 2H), 7.57 (m,2H), 7.51 (s, 5H), 6.99 (d, J=7.8 Hz, 1H), 6.12 (dd, J=7.8, 2.7 Hz, 1H),5.99 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.33 (br s, 2H), 3.68 (s, 3H),3.52-3.48 (m, 2H), 3.12-3.08 (m, 2H); ESI MS m/z 420 [M+H]⁺; HPLC(Method B) 97% (AUC), t_(R)=13.99 min.

Example 9 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenethylpyridin-2(1H)-onedihydrochloride

a) tert-Butyl5-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

The compound was prepared from tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.548 mmol) and 4-phenethylpyridin-2(1H)-one (109 mg, 0.548mmol) according to the procedure in Example 1 (step c). Purification byflash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20to 50:50 to 25:75 then 0:100) provided the title compound (126 mg, 48%)as a yellow solid:

¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.2 Hz, 1H), 7.34-7.30 (m, 4H),7.24-7.20 (m, 3H, partially masked by solvent), 7.03 (d, J=7.8 Hz, 1H),6.52 (s, 1H), 6.10 (dd, J=7.9, 1.7 Hz, 1H), 4.65 (br s, 2H), 3.84 (br s,2H), 3.63 (s, 3H), 2.98-2.93 (m, 2H), 2.84-2.81 (m, 4H), 1.51 (s, 9H).

b)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenethylpyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(120 mg, 0.248 mmol) was dissolved in MeOH (1.5 mL) and 2 N HCl in Et₂O(5 mL) was added. The reaction was allowed to proceed for 3 h. Theresulting precipitate was collected by filtration and washed with Et₂Oto provide the title compound (90 mg, 80%) as a yellow solid: mp282-286° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.70 (d, J=6.9 Hz, 1H), 7.62 (d,J=8.3 Hz, 1H), 7.52 (s, 1H), 7.33-7.26 (m, 4H), 7.22 (t, J=7.2 Hz, 1H),7.09 (dd, J=8.3, 1.6 Hz, 1H), 6.59-6.56 (m, 2H), 4.50 (s, 2H), 3.76 (s,3H), 3.70 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.0 Hz, 2H), 3.04-3.01 (m, 2H),2.98-2.95 (m, 2H); ESI MS m/z 384 [M+H]⁺; HPLC (Method B)>99% (AUC),t_(R)=13.3 min.

Example 10 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onedihydrochloride

a) tert-Butyl5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

The compound was prepared from tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(153 mg, 0.418 mmol) and 4-(4-(trifluoromethy)phenyl)pyridine-2(1H)-one(100 mg g, 0.418 mmol) according to the procedure in Example 1 (step c).Purification by flash column chromatography (silica gel, hexanes/EtOAc,100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound(98 mg, 45%) as a yellow/green solid: ¹H NMR (500 MHz, CDCl₃) δ 7.75 (s,4H), 7.57-7.53 (m, 2H), 7.37 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.92 (s,1H), 6.50 (d, J=6.7 Hz, 1H), 4.67 (s, 2H), 3.86 (br s, 2H), 3.60 (s,3H), 2.84 (br s, 2H), 1.51 (s, 9H).

b)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(95 mg, 0.18 mmol) was dissolved in MeOH (2 mL) and 2 N HCl in Et₂O (10mL) was added. The reaction was allowed to proceed for 3 h. Theresulting precipitate was collected by filtration and washed with Et₂Oto provide the title compound (45 mg, 50%) as a pale yellow solid: mp318-323° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.95 (d, J=8.2 Hz, 2H), 7.84 (d,J=8.2 Hz, 2H), 7.81 (d, J=7.1 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.57 (s,1H), 7.14 (dd, J=8.3, 1.3 Hz, 1H), 6.96 (d, J=1.6 Hz, 1H), 6.87 (dd,J=7.1, 1.7 Hz, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 3.68 (t, J=6.1 Hz, 2H),3.22 (t, J=6.1 Hz, 2H); ESI MS m/z 424 [M+H]⁺; HPLC (Method B) 97.6%(AUC), t_(R)=13.9 min.

Example 11 Preparation of4-(4-Chlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) 4-(4-Chlorophenyl)pyridine 1-oxide

Beilstein Registry Number 5510914

4-Chloropyridine-N-oxide (1.5 g, 12 mmol), 4-chlorophenylboronic acid(2.7 g, 17 mmol) and K₂CO₃ (4.78 g, 34.6 mmol) were suspended in DMSO(15 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)) (225 mg, 0.276 mmol) was added. The reaction mixture wasplaced under vacuum for 20 min and then flushed with N₂. This processwas repeated, and the reaction mixture was heated to 120° C. for 3 h,cooled and partitioned between ethyl acetate and brine. The aqueousphase was removed, and the organic phase was washed with brine, driedover Na₂SO₄, filtered and concentrated to dryness. Purification by flashcolumn chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to50:50 then 25:75 followed by methylene chloride/MeOH 100:0 to 95:5 then90:10) provided the title compound (1.05 g, 44%) as a grey solid: ¹H NMR(300 MHz, CDCl₃) δ 8.26 (d, J=7.1 Hz, 2H), 7.58-7.43 (m, 6H).

b) 4-(4-Chlorophenyl)pyridin-2(1H)-one

4-(4-Chlorophenyl)pyridine 1-oxide (1.04 g, 5.07 mmol) and aceticanhydride (25 mL) were heated to reflux for 24 h. The mixture was thenconcentrated, and 1 N NaOH (10 mL) in MeOH (10 mL) was added. Thereaction mixture was heated to reflux for 1 h, then cooled,concentrated, and purified by flash column chromatography (silica gel,methylene chloride/MeOH 100:0 to 98:2 to 95:5 then 90:10) providing thetitle compound (500 mg, 48%) as an off-white solid: ¹H NMR (300 MHz,CDCl₃) δ 11.64 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H),7.46 (d, J=6.8 Hz, 1H), 6.60 (d, J=1.4 Hz, 1H), 6.50 (dd, J=6.9, 1.8 Hz,1H).

c) tert-Butyl7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

The compound was prepared from tert-Butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(250 mg, 0.685 mmol) and 4-(4-chlorophenyl)pyridine-2(1H)-one (100 mg,0.418 mmol) according to the procedure in Example 1 (step c).Purification by flash column chromatography (silica gel, hexanes/EtOAc,100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound(59 mg, 18%) as a solid, that contained an impurity: ESI MS m/z 490[M+H]⁺.

d)4-(4-Chlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(59 mg, 0.12 mmol) was dissolved in MeOH (0.5 mL) and 2 N HCl in Et₂O (3mL) was added. The reaction was allowed to proceed for 3 h. The mixturewas concentrated and purified by preparative HPLC. Conversion to the HClsalt (2 N HCl in Et₂O) provided the title compound (22 mg, 40%) as apale yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 7.80-7.78 (m, 3H), 7.66 (d,J=8.5 Hz, 1H), 7.58-7.57 (m, 3H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 6.94 (d,J=1.8 Hz, 1H), 6.87 (dd, J=7.1, 1.9 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H),4.53 (s, 2H), 3.79 (s, 3H), 3.72 (t, J=5.9 Hz, 2H), 3.25 (t, J=5.9 Hz,2H); ESI MS m/z 390 [M+H]⁺; HPLC (Method B) 98.2% (AUC), t_(R)=16.3 min.

Example 12 Preparation of4-(2,4-Dichlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-(4-(2,4-dichlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

The compound was prepared from tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.548 mmol) and 4-(2,4-dichlorophenyl)pyridine-2(1H)-one (132mg, 0.548 mmol) according to the procedure in Example 1 (step c).Purification by flash column chromatography (silica gel, hexanes/EtOAc,100:0 to 80:20 to 50:50 then 25:75) provided the title compound (56 mg,20%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.56-7.52 (m, 2H),7.47 (d, J=7.0 Hz, 1H), 7.39-7.32 (m, 3H), 7.10 (br s, 1H), 6.69 (s,1H), 6.35 (d, J=5.7 Hz, 1H), 4.66 (s, 2H), 3.85 (br s, 2H), 3.65 (s,3H), 2.84 (br s, 2H), 1.51 (s, 9H).

b)4-(2,4-Dichlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl7-(4-(2,4-dichlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(56 mg, 0.11 mmol) was dissolved in MeOH (1 mL) and 2 N HCl in Et₂O (5mL) was added. The reaction was allowed to proceed for 3 h. The mixturewas concentrated and purified by preparative HPLC. Conversion to the HClsalt (2 N HCl in Et₂O) provided the title compound (22 mg, 42%) as ayellow solid: mp 321-324° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.80 (d, J=7.0Hz, 1H), 7.70 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.54 (s,2H), 7.13 (d, J=7.0 Hz, 1H), 6.73 (s, 1H), 6.61 (d, J=7.2 Hz, 1H), 4.54(s, 2H), 3.80 (s, 3H), 3.72 (t, J=6.0 Hz, 2H), 3.26 (t, J=5.9 Hz, 2H);ESI MS m/z 424 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=14.1 min.

Example 13 Preparation of4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

To a mixture of 4-bromophenylhydryzine hydrochloride (1.00 g, 4.47 mmol)and tert-butyl 4-oxopiperidine-1-carboxylate (0.89 g, 4.5 mmol) wereadded EtOH (10 mL) and conc. HCl (3 mL). The reaction mixture was heatedto 90° C. and stirred at 90° C. until the reaction was complete. Thenthe mixture was concentrated and the residue was dissolved in CH₂Cl₂ (10mL) and CH₃OH (5 mL). To the above solution were added Boc₂O (1.46 g,6.69 mmol), TEA (0.94 mL, 6.7 mmol) and DMAP (55 mg, 0.45 mmol). Thereaction mixture was stirred at room temperature until it was complete.The mixture was concentrated and the residue was dissolved in CH₂Cl₂,washed with H₂O and brine, dried with Na₂SO₄, filtered and concentrated.Purification by flash column chromatography (silica gel, hexanes/EtOAc,1:1) gave the title compound (1.12 g, 72%) as a yellow foam: ¹H NMR (500MHz, CDCl₃) δ 7.89 (br s, 1H), 7.57 (s, 1H), 7.17-7.24 (m, 2H), 4.58 (s,2H), 3.81 (m, 2H), 2.83 (m, 2H), 1.5 (s, 9H); ESI MS m/z 351 [M+H]⁺.

b) tert-Butyl8-4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2-(5H)-carboxylate

To a solution of tert-butyl8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.53 g,1.5 mmol) in DMF (6 mL) was added NaH (60% weight dispersion in mineraloil, 91 mg, 2.3 mmol) and CH₃I (0.14 mL, 2.3 mmol). The reaction mixturewas stirred at room temperature until the reaction was complete. Thenthe reaction was quenched with H₂O and extracted with CH₂Cl₂. Theorganic layer was washed with H₂O and 5% LiCl, dried with Na₂SO₄,filtered and concentrated to give tert-butyl8-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate,which was used directly without purification.

To a mixture of tert-butyl8-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.48 g, 1.3 mmol), 4-(benzyloxy)pyridin-2(1H)-one (264 mg, 1.31 mmol),8-hydroxyquinoline (29 mg, 0.20 mmol), K₂CO₃ (217 mg, 1.57 mmol) and CuI(38 mg, 0.20 mmol) was added DMSO (5 mL). The reaction mixture wasdegassed and back-filled with N₂. The reaction mixture was heated to130° C. and stirred at 130° C. overnight. After it was cooled, themixture was filtered through a layer of Celite. The filtrate was dilutedwith CH₂Cl₂, washed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered,and concentrated. Purification by flash column chromatography (silicagel, 5% CH₃OH in CH₂Cl₂) gave the title compound (0.28 g, 44%) as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.36-7.29 (m, 8H), 7.13 (d,J=8.0 Hz, 1H), 6.09 (d, J=2.0 Hz, 1H), 6.03 (dd, J=7.5, 2.0 Hz, 1H),5.05 (s, 2H), 4.61 (s, 2H), 3.84 (m, 2H), 3.66 (s, 3H), 2.82 (m, 2H),1.49 (s, 9H); ESI MS m/z 486 [M+H]⁺.

c)4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

To a solution of tert-butyl8-4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2-(5H)-carboxylate(180 mg, 0.37 mmol) in CH₃OH (2 mL) was added 1 N HCl in Et₂O (2 mL).The reaction mixture was stirred at room temperature until the reactionwas complete. The resulting solid was dried under vacumn to give thetitle compound (142 mg, 91%) as a yellow solid: mp 280-285° C.(decompose); ¹H NMR (500 MHz, CD₃OD) δ 7.59 (d, J=7.5 Hz, 1H), 7.54 (d,J=9.0 Hz, 1H), 7.48-7.40 (m, 5H), 7.38-7.36 (m, 1H), 7.17 (dd, J=8.5,1.5 Hz, 1H), 6.33 (dd, J=7.5, 2.5 Hz, 1H), 6.16 (d, J=2.5 Hz, 1H), 5.20(s, 2H), 4.45 (s, 2H), 3.77 (s, 3H), 3.67 (t, J=6.0 Hz, 2H), 3.21 (t,J=6.0 Hz, 2H); ESI MS m/z 386 [M+H]⁺; HPLC (Method B) 98.8% (AUC),t_(R)=12.9 min.

Example 14 Preparation of4-(Benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one(100 mg, 0.26 mmol) in CH₃OH (3 mL) was added formaldehyde (30 L, 0.29mmol) and NaBH(OAc)₃ (110 mg, 0.52 mmol). The reaction mixture wasstirred at room temperature until the reaction was complete. Then themixture was concentrated and the residue was dissolved in CH₂Cl₂. Theorganic layer was washed with H₂O and 5% LiCl, dried with Na₂SO₄,filtered and concentrated. Purification by flash column chromatography(silica gel, 10% CH₃OH in CH₂Cl₂) gave4-(benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one(102 mg, 98%) as a yellow solid. The free base was converted to the HClsalt to give the title compound (100 mg, 90%) as a yellow solid: mp264-268° C. (decompose); ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (s, 1H),7.56-7.36 (m, 8H), 7.10 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 3.0Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (m, 1H), 4.27 (m,1H), 3.78 (m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 3.18 (m, 2H), 2.97 (s,3H); ESI MS m/z 400 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.9 min.

Example 15 Preparation of2-(Pyrrolidin-1-yl)ethyl-7-4-(benzyloxy)-2-oxopyridin-1(2H)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylatehydrochloride

To a solution of4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (100 mg, 0.24 mmol) in DMSO (2 mL) was added1-(2-chloroethyl)pyrrolidine hydrochloride (53 mg, 0.29 mmol) and Cs₂CO₃(313 mg, 1.06 mmol). The reaction mixture was stirred at roomtemperature under Ar until the reaction was complete. The reaction wasquenched with water and extracted with CH₂Cl₂. The organic layer waswashed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered, andconcentrated. Purification by flash column chromatography (silica gel,5% CH₃OH in CH₂Cl₂) gave2-(pyrrolidin-1-yl)ethyl-7-4-(benzyloxy)-2-oxopyridin-1(2H)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(56 mg, 44%) as a yellow foam. The free base was converted to the HClsalt to give the title compound (44 mg, 73%) as a yellow solid: mp95-97° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.78-7.75 (m, 1H), 7.57-7.54 (m,1H), 7.49-7.37 (m, 6H), 7.04-7.01 (m, 1H), 6.55-6.52 (m, 1H), 6.33-6.31(m, 1H), 5.26 (s, 2H), 4.80-4.73 (m, 2H), 4.49-4.48 (m, 2H), 3.94-3.93(m, 2H), 3.82-3.72 (m, 2H), 3.69 (s, 3H), 3.58-3.57 (m, 2H), 3.20-3.14(m, 2H), 2.98-2.94 (m, 2H), 2.15-1.99 (m, 4H); ESI MS m/z 527 [M+H]⁺;HPLC (Method B)>99% (AUC), t_(R)=13.8 min.

Example 16 Preparation of4-(Benzyloxy)-1-(2-(2-(dimethylamino)acetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(100 mg, 0.26 mmol) in CH₂Cl₂ (2 mL) was added 2-chloroacetyl chloride(29 μL, 0.36 mmol) and Et₃N (0.1 mL, 0.7 mmol). The reaction mixture wasstirred at room temperature until the reaction was complete. After thesolvent was removed, the residue was dissolved in DMF. To the DMFsolution was added (CH₃)₂NH (64 μL, 1.2 mmol) and K₂CO₃ (166 mg, 1.2mmol). The reaction mixture was heated to 70° C. and stirred at 70° C.until the reaction was complete. After it was cooled, the reaction wasquenched with water and extracted with CH₂Cl₂. The organic layer waswashed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered, andconcentrated. Purification by flash column chromatography (silica gel,10% CH₃OH in CH₂Cl₂) gave4-(benzyloxy)-1-(2-(2-(dimethylamino)acetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(58 mg, 51%) as a yellow foam. The free base was converted to the HClsalt to give the title compound (31 mg, 50%) as a yellow solid and as amixture of rotamers: mp 135-140° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.75-7.71(m, 1H), 7.59-7.55 (m, 1H), 7.49-7.37 (m, 6H), 7.05-7.01 (m, 1H),6.49-6.45 (m, 1H), 6.28-6.26 (m, 1H), 5.24 (s, 2H), 4.87 (br s, 1H),4.69 (br s, 1H), 4.44-4.41 (m, 2H), 4.11-4.07 (m, 1H), 3.85-3.82 (m,1H), 3.70 (2×s, 3H), 3.06-2.92 (m, 2H), 2.97-2.94 (2×s, 6H); ESI MS m/z471 [M+H]⁺; HPLC (Method B) 97.0% (AUC), t_(R)=13.2 min.

Example 17 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-onehydrochloride

To a solution of4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(100 mg, 0.26 mmol) in DMF (3 mL) was added2-chloro-1-(pyrrolidin-1-yl)ethanone (77 mg, 0.52 mmol) and K₂CO₃ (72mg, 0.52 mmol). The reaction mixture was heated to 70° C. and stirred at70° C. until the reaction was complete. After it was cooled, thereaction was quenched with water and extracted with CH₂Cl₂. The organiclayer was washed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered, andconcentrated. Purification by flash column chromatography (silica gel,5% CH₃OH in CH₂Cl₂) gave4-(benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one(35 mg, 27%) as a yellow foam. The free base was converted to the HClsalt to the give title compound (30 mg, 80%) as a yellow solid: mp162-166° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.60 (d, J=7.5 Hz, 1H), 7.56 (d,J=8.0 Hz, 1H), 7.49-7.35 (m, 6H), 7.06 (dd, J=8.5, 1.5 Hz, 1H), 6.33(dd, J=7.5, 3.0 Hz, 1H), 6.16 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d,J=14.5 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m,1H), 3.75 (s, 3H), 3.68-3.65 (m, 1H), 3.54 (t, J=7.0 Hz, 2H), 3.49-3.45(m, 2H), 3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H); ESI MS m/z 497 [M+H]⁺;HPLC (Method B) 97.9% (AUC), t_(R)=13.4 min.

Example 18 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(3-(pyrrolidin-1-yl)propanoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-onehydrochloride

To a solution of4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(100 mg, 0.26 mmol) in DMF (3 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HATU) (148 mg, 0.389 mmol),3-(pyrrolidin-1-yl)propanoic acid hydrochloride (56 mg, 0.31 mmol), andEt₃N (73 μL, 0.52 mmol). The reaction mixture was stirred at roomtemperature under Ar until the reaction was complete. The reaction wasquenched with water and extracted with CH₂Cl₂. The organic layer waswashed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered andconcentrated. Purification by flash column chromatography (silica gel,5% CH₃OH in CH₂Cl₂) gave4-(benzyloxy)-1-(5-methyl-2-(3-(pyrrolidin-1-yl)propanoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-oneas a yellow foam. The free base was converted to the HCl salt to givethe title compound (75 mg, 86%) as a yellow solid: mp 110-115° C.; ¹HNMR (500 MHz, CD₃OD) δ 7.79-7.76 (m, 1H), 7.61-7.55 (m, 1H), 7.49-7.36(m, 6H), 7.05-7.02 (m, 1H), 6.55-6.52 (m, 1H), 6.33-6.32 (m, 1H), 5.26(s, 2H), 4.06 (t, J=5.5 Hz, 1H), 3.94 (t, J=5.5 Hz, 1H), 3.70-3.69 (m,5H), 3.54-3.50 (m, 2H), 3.18-2.89 (m, 8H), 2.18-2.04 (m, 4H); ESI MS m/z511 [M+H]⁺; HPLC (Method B) 97.7% (AUC), t_(R)=13.6 min.

Example 19 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 18, but substituting1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid for3-(pyrrolidin-1-yl)propanoic acid hydrochloride, a yellow solid wasobtained in 78% yield (118 mg). The yellow solid was dissolved in CH₃OH(3 mL) and was treated with 1 N HCl in Et₂O (2 mL). The resulting solidwas isolated by filtration and dried under vacuum to give the titlecompound (90 mg, 90%) as a green-yellow powder: ¹H NMR (500 MHz, CD₃OD)δ 7.75-7.72 (m, 1H), 7.63-7.55 (m, 1H), 7.49-7.36 (m, 6H), 7.05-7.02 (m,1H), 6.51-6.46 (m, 1H), 6.29-6.27 (m, 1H), 5.25 (s, 2H), 4.79-4.76 (m,2H), 4.14-3.97 (m, 2H), 3.87-3.82 (m, 1H), 3.71-3.69 (m, 4H), 3.60-3.50(m, 1H), 3.45-3.36 (m, 3H), 3.04-3.03 (m, 1H), 2.94-2.92 (m, 1H),2.52-2.36 (m, 1H), 2.18-2.00 (m, 1H); ESI MS m/z 483 [M+H]⁺; HPLC(Method B) 98.1% (AUC), t_(R)=13.2 min.

Example 20 Preparation of(R)-4-(Benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 19, but substituting(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid for1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid, the title compound(67 mg, 50%) was obtained as a yellow solid and as a mixture ofrotamers: ¹H NMR (500 MHz, CD₃OD) δ 7.82-7.79 (m, 1H), 7.66-7.56 (m,1H), 7.49-7.36 (m, 6H), 7.07-7.03 (m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd,J=5.0, 2.5 Hz, 1H), 5.28 (s, 2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, 1H),3.97-3.95 (m, 1H), 3.71-3.69 (2×s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94 (m,2H), 2.70-2.57 (m, 1H), 2.17-1.85 (m, 3H); ESI MS m/z 483 [M+H]⁺; HPLC(Method B)>99% (AUC), t_(R)=13.3 min.

Example 21 Preparation of(S)-4-(Benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 20, but substituting(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid for(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid, the titlecompound (47 mg, 72%) was obtained as a yellow solid and as a mixture ofrotamers: ¹H NMR (500 MHz, CD₃OD) δ 7.82-7.79 (m, 1H), 7.66-7.56 (m,1H), 7.49-7.36 (m, 6H), 7.07-7.03 (m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd,J=5.0, 2.5 Hz, 1H), 5.28 (s, 2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, 1H),3.97-3.95 (m, 1H), 3.71-3.69 (2×s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94 (m,2H), 2.70-2.57 (m, 1H), 2.17-1.85 (m, 3H); ESI MS m/z 483 [M+H]⁺; HPLC(Method B)>99% (AUC), t_(R)=13.3 min.

Example 22 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (105 mg, 0.197 mmol) in CH₃OH (3 mL) was added Et₃N (40μL, 0.29 mmol), formaldehyde (23 μL, 0.29 mmol), and NaBH(OAc)₃ (86 mg,0.41 mmol). The reaction mixture was stirred at room temperature untilthe reaction was complete. Then the mixture was concentrated and theresidue was dissolved in CH₂Cl₂. The organic layer was washed with H₂Oand 5% LiCl, dried with Na₂SO₄, filtered and concentrated. Purificationby flash column chromatography (silica gel, 10% CH₃OH in CH₂Cl₂) gave4-(benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(60 mg, 60%) as a yellow solid. The free base was converted to the HClsalt to give the title compound (43 mg, 80%) as a yellow solid and as amixture of rotamers: mp 132-136° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.61-7.33(m, 8H), 7.02-6.98 (m, 1H), 6.29-6.27 (m, 1H), 6.12-6.11 (m, 1H), 5.17(s, 2H), 4.79-4.76 (m, 2H), 4.09-3.97 (m, 2H), 3.81-3.79 (m, 1H),3.69-3.67 (m, 4H), 3.49-3.42 (m, 1H), 3.22-3.16 (m, 2H), 3.00 (m, 1H),2.92-2.91 (m, 1H), 2.81-2.78 (2×s, 3H), 2.52-2.36 (m, 1H), 2.18-2.00 (m,1H); ESI MS m/z 497 [M+H]⁺; HPLC (Method B) 98.7% (AUC), t_(R)=13.6 min.

Example 23 Preparation of(R)-4-(Benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 22, but substituting(R)-4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride for4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride, the title compound (80 mg, 67%) was obtained as a yellowsolid and as a mixture of rotamers: mp 158-162° C.; ¹H NMR (500 MHz,CD₃OD) δ 7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30 (dd, J=7.5, 2.5 Hz,1H), 6.13 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.80-4.70 (m, 2H), 4.12-4.09(m, 1H), 3.92-3.90 (m, 1H), 3.78-3.72 (m, 1H), 3.69-3.68 (2s, 3H),3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H), 3.07-3.00 (m, 2H), 2.96-2.94 (2s,3H), 2.79-2.65 (m, 1H), 2.21-2.09 (m, 1H), 2.09-1.86 (m, 2H); ESI MS m/z497 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=13.4 min.

Example 24 Preparation of(S)-4-(Benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 22, but substituting(S)-4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride for4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride, the title compound (40 mg, 61%) was obtained as a yellowsolid and as a mixture of rotamers: mp 154-160° C.; ¹H NMR (500 MHz,CD₃OD) δ 7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30 (dd, J=7.5, 2.5 Hz,1H), 6.13 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.80-4.70 (m, 2H), 4.12-4.09(m, 1H), 3.92-3.90 (m, 1H), 3.78-3.72 (m, 1H), 3.69-3.68 (2s, 3H),3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H), 3.07-3.00 (m, 2H), 2.96-2.94 (2×s,3H), 2.79-2.65 (m, 1H), 2.21-2.09 (m, 1H), 2.09-1.86 (m, 2H); ESI MS m/z497 [M+H]⁺; HPLC (Method B) 98.9% (AUC), t_(R)=13.3 min.

Example 25 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-fluorophenyl)pyridine-2(1H)-onehydrochloride a) tert-Butyl5-methyl-7-(2-oxo-4-(trifluoromethylsulfonyloxy)pyridine-1(2H)-yl)3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

To a solution of tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.98 g, 2.0 mmol) in CH₃OH (30 mL) was added 5% Pd/C (0.3 g) andammonium formate (0.32 g, 5 mmol) under Ar atmosphere. The reactionmixture was heated to 90° C. and stirred at 90° C. until the reactionwas complete. After it was cooled, the reaction mixture was filteredthrough a layer of Celite. The solvent was concentrated to givetert-butyl7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate,which was used directly without purification.

To a solution of tert-butyl7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(800 mg, 2.02 mmol) in THF (10 mL) was added LiN(SiMe₃)₂ (2.6 mL, 2.6mmol) followed by PhN(Tf)₂ (0.94 g, 2.6 mmol) under Ar atmosphere. Thereaction mixture was stirred at room temperature until the reaction wascomplete. Then the mixture was concentrated and the residue was purifiedby flash column chromatography (silica gel, hexanes/EtOAc, 1:1) to givethe title compound (0.42 g, 40%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.57-7.53 (m, 2H), 7.30 (d, J=1.5 Hz, 1H), 7.02-6.99 (m, 1H),6.60 (d, J=2.7 Hz, 1H), 6.27 (dd, J=7.8, 2.7 Hz, 1H), 4.65 (s, 2H), 3.85(m, 2H), 3.65 (s, 3H), 2.84 (m, 2H), 1.51 (s, 9H); ESI MS m/z 528[M+H]⁺.

b)1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-fluorophenyl)pyridine-2(1H)-onehydrochloride

To a solution of tert-butyl5-methyl-7-(2-oxo-4-(trifluloromethylsulfonyloxy)pyridine-1-(2H)-yl)3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(100 mg, 0.19 mmol) in DMSO (2 mL) was added 4-fluorophenylboronic acid(66 mg, 0.48 mmol), K₂CO₃ (66 mg, 0.48 mmol), and PdCl₂(dppf) (14 mg,0.019 mmol). The reaction mixture was degassed, then back-filled withN₂. The reaction mixture was stirred at 80° C. in a pre-heated oil bathfor 2 hours. After cooling, the reaction was quenched with water andextracted with CH₂Cl₂. The organic layer was washed with H₂O and 5%LiCl, dried with Na₂SO₄, filtered and concentrated. Purification byflash column chromatography (silica gel, 5% CH₃OH in CH₂Cl₂) gave ayellow solid (120 mg, >100%). The solid was dissolved in CH₃OH (2 mL)and treated with 1 N HCl in Et₂O (1.9 mL). The reaction mixture wasstirred at room temperature until the reaction was complete. After thesolvent was removed, the resulting solid was dissolved in CH₃OH (3 mL).Et₃N (40 μL), formaldehyde (22 μL, 0.29 mmol), and NaBH(OAc)₃ were addedsequentially. The reaction mixture was stirred at room temperature untilthe reaction was complete. The solvent was removed and the residue wasdissolved in CH₂Cl₂. The organic layer was washed with H₂O and 5% LiCl,dried with Na₂SO₄, filtered and concentrated. Purification by flashcolumn chromatography (silica gel, 5% CH₃OH in CH₂Cl₂) gave1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-fluorophenyl)pyridine-2(1H)-one(37 mg 50% yield over three steps) as a yellow solid. The free base wasconverted to the HCl salt to give the title compound (36.5 mg, 91%) as ayellow solid: mp 276-280° C. (decompose); ¹H NMR (500 MHz, CD₃OD) δ7.82-7.79 (m, 2H), 7.75 (d, J=7.0 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.56(d, J=1.5 Hz, 1H), 7.29-7.25 (m, 2H), 7.14 (dd, J=8.5, 1.5 Hz, 1H), 6.88(d, J=2.0 Hz, 1H), 6.82 (dd, J=7.0, 2.0 Hz, 1H), 4.77 (d, J=14.0 Hz,1H), 4.41 (d, J=14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.76 (s, 3H), 3.66-3.60(m, 1H), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 388 [M+H]⁺; HPLC (MethodB) 98.1% (AUC), t_(R)=12.8 min.

Example 26 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trifluoromethylphenyl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 25 (step b), but substituting4-trifluoromethylphenylboronic acid for 4-fluorophenylboronic acid, thetitle compound (47 mg, 53%) was obtained as a yellow solid: mp 270-274°C.; ¹H NMR (500 MHz, CD₃OD) δ 7.95 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz,2H), 7.80 (d, J=7.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.5 Hz,1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.96 (d, J=1.5 Hz, 1H), 6.87 (dd,J=7.5, 2.0 Hz, 1H), 4.78 (d, J=14.0 Hz, 1H), 4.41 (d, J=14.0 Hz, 1H),3.93-3.90 (m, 1H), 3.77 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15(s, 3H); ESI MS m/z 438 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=13.8min.

Example 27 Preparation of4-(4-Chlorophenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-pyridin-2(1H)-onehydrochloride

Following the procedure of Example 25 (step b), but substituting4-chlorophenylboronic acid for 4-fluorophenylboronic acid, the titlecompound (55 mg, 65%) was obtained as a yellow solid: mp 276-280° C.; ¹HNMR (500 MHz, CD₃OD) δ 7.77-7.75 (m, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.57(d, J=2.0 Hz, 1H), 7.56-7.54 (m, 2H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.91(d, J=2.0 Hz, 1H), 6.84 (dd, J=7.0, 2.0 Hz, 1H), 4.78 (d, J=14.0 Hz,1H), 4.41 (d, J=14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.77 (s, 3H), 3.66-3.60(m, 1H), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 404 [M+H]⁺; HPLC (MethodB) 98% (AUC), t_(R)=13.4 min.

Example 28 Preparation of4-(4-Chloro-2-fluorophenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-pyridin-2(1H)-onehydrochloride

Following the procedure of Example 25 (step b), but substituting4-chloro-2-fluorophenylboronic acid for 4-fluorophenylboronic acid, thetitle compound (20 mg, 32%) was obtained as a yellow solid: mp 270-274°C.; ¹H NMR (500 MHz, CD₃OD) δ 7.76 (d, J=7.0 Hz, 1H), 7.66-7.57 (m, 2H),7.57 (d, J=2.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.15 (dd, J=8.5, 2.0 Hz, 1H),6.84 (s, 1H), 6.73-6.71 (m, 1H), 4.77 (d, J=14.0 Hz, 1H), 4.41 (d,J=14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.76 (s, 3H), 3.64-3.61 (m, 1H), 3.27(m, 2H), 3.15 (s, 3H); ESI MS m/z 422 [M+H]⁺; HPLC (Method B)>99% (AUC),t_(R)=12.9 min.

Example 29 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(2-fluoro-4-methoxyphenyl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 25 (step b), but substituting2-fluoro-4-methoxyphenylboronic acid for 4-fluorophenylboronic acid, thetitle compound (46 mg, 53%) was obtained as a yellow solid: mp 280-282°C.; ¹H NMR (500 MHz, CD₃OD) δ 7.72 (d, J=7.0 Hz, 1H), 7.63-7.56 (m, 3H),7.15 (dd, J=8.5, 1.5 Hz, 1H), 6.92 (dd, J=8.5, 2.5 Hz, 1H), 6.87 (dd,J=13.0, 2.0 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J=7.0 Hz, 1H), 4.77 (d,J=14.0 Hz, 1H), 4.41 (d, J=14.0 Hz, 1H), 3.94-3.90 (m, 1H), 3.88 (s,3H), 3.76 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15 (s, 3H); ESI MSm/z 418 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.9 min.

Example 30 Preparation of4-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 2-(6-Bromo-1H-indol-3-yl)ethanamine

Beilstein Registry Number 6056308

3-Bromophenylhydrazine hydrochloride (20.0 g, 85.8 mmol) was reactedaccording to the procedure of Mascal et al. (Rinehart, Kenneth L.;Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy; Mascal, Mark; etal. J. Am. Chem. Soc. 1987, 109, 3378-3387) to provide the titlecompound as a 1:1 mixture of the 6-bromo and 7-bromo-regioisomers (13.2g, 65%), obtained as an orange solid: ESI MS m/z 239 [M+H]⁺.

b) 7-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Beilstein Registry Number 5935540

2-(6-Bromo-1H-indol-3-yl)ethanamine (13.2 g, 55.2 mmol) was reactedaccording to the procedure of Mascal et al. (Rinehart, Kenneth L.;Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy; Mascal, Mark; etal. J. Am. Chem. Soc. 1987, 109, 3378-3387) to provide the titlecompound as a 1:1 mixture of the 7-bromo and 8-bromo-regioisomers (8.8g, 63%), obtained as an orange solid: ESI MS m/z 251 [M+H]⁺.

c) tert-Butyl7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

7-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (8.81 g, 35.1 mmol,present as a mixture with the 8-bromo regioisomer) was suspended inCH₂Cl₂ (100 mL) and THF (10 mL). Boc anhydride (7.83 g, 38.6 mmol) and acatalytic amount of 4-(dimethylamino)pyridine (DMAP) were added. After24 h, the mixture was concentrated. Purification by flash columnchromatography (silica gel, hexanes/ethyl acetate, 97:3 to 70:30)separated the 7- and 8-regioisomers and gave the title compound (3.37 g,27%) as a white powder: ¹H NMR (500 MHz, CDCl₃) δ 7.94 (br s, 1H), 7.45(d, J=1.6 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.19 (dd, J=8.3, 1.3 Hz, 1H),4.61 (br s, 2H), 3.75 (br s, 2H), 2.76 (br s, 2H), 1.50 (s, 9H).

d) tert-Butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(1.96 g, 5.58 mmol) was dissolved in DMF (20 mL), and sodium hydride(60% weight dispersion in mineral oil, 330 mg, 8.37 mmol) was added.After 30 minutes, methyl iodide (0.52 mL, 8.4 mmol) was added, and thereaction stirred for a further 2 h. The mixture was diluted withmethylene chloride and washed with 5% lithium chloride solution (5×),dried and concentrated. Purification by flash column chromatography(silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the titlecompound (1.75 g, 86%) as a white powder: ¹H NMR (500 MHz, CD₃OD) δ 7.41(d, J=1.5 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H),4.60 (br s, 2H), 3.73 (br s, 2H), 3.59 (s, 3H), 2.76 (br s, 2H), 1.50(s, 9H).

e) 7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(1.75 g, 4.79 mmol) was dissolved in CH₂Cl₂ (10 mL) and trifluoroaceticacid (TFA) (10 mL) was added. After stirring for 1 h, the mixture wasdiluted with methylene chloride (50 mL), washed with saturated Na₂CO₃solution, dried over sodium sulfate and concentrated to provide thetitle compound (1.24 g, 97%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.41 (d, J=1.4 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.3, 1.4 Hz,1H), 4.01 (s, 2H), 3.55 (s, 3H), 3.15 (t, J=6.0 Hz, 2H), 2.72 (t, J=5.7Hz, 2H).

f) 7-Bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.24 g, 4.68mmol) was dissolved in a mixture of MeOH (20 mL) and CH₂Cl₂ (5 mL) andformaldehyde (0.56 mL, 37% aqueous solution) was added. After stirringfor 1 h, NaBH(OAc)₃ (1.98 g, 9.34 mmol) was added and the mixturestirred for a further 10 minutes. The mixture was diluted with methylenechloride (50 mL), washed with saturated Na₂CO₃ solution, concentratedand purified by flash column chromatography (40 g ISCO column elutingwith methylene chloride and a methanol/ammonia mixture (10:1); gradient100% methylene chloride to 90% methylene chloride over 30 min at 40mL/min) to provide the title compound (1.15 g, 88%) as a white powder:¹H NMR (500 MHz, CDCl₃) δ 7.40 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.4 Hz,1H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 3.61 (s, 2H), 3.55 (s, 3H), 2.86-2.76(m, 4H), 2.56 (s, 3H).

g)4-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

A stirred solution of7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (250 mg,0.895 mmol) in DMSO (4 mL) under nitrogen was treated sequentially with4-(benzyloxy)pyridin-2(1H)-one (180 mg, 0.895 mmol), 8-hydroxyquinoline(20 mg, 0.14 mmol), CuI (196 mg, 1.04 mmol) and K₂CO₃ (142 mg, 1.04mmol). The mixture was placed under vacuum for 30 minutes and thenflushed with nitrogen. After stirring overnight at 130° C., the mixturewas allowed to cool to room temperature, diluted with CH₂Cl₂, washedwith brine, dried over Na₂SO₄ and concentrated. Purification by flashcolumn chromatography (12 g ISCO column eluting with methylene chlorideand a methanol/ammonia mixture (10:1); gradient 100% methylene chlorideto 80% methylene chloride over 30 min at 25 mL/min) provided thefree-base. This was dissolved in methylene chloride (2 mL) and treatedwith 2 N HCl in Et₂O (1 equivalent) and the mixture was concentrated toprovide the title compound (131 mg, 33%) as a yellow solid: mp 270-274°C.; ¹H NMR (500 MHz, CD₃OD) δ 7.67-7.63 (m, 2H), 7.50-7.40 (m, 3H),7.43-7.35 (m, 3H), 7.08 (dd, J=8.3, 1.6 Hz, 1H), 6.40 (dd, J=7.5, 2.6Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.81-4.80 (m, 1H), 4.58(d, J=15.3 Hz, 1H), 3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.49 (m, 1H),3.21-3.16 (m, 5H); ESI MS m/z 400 [M+H]⁺; HPLC (Method B)>98.9% (AUC),t_(R)=13.0 min.

Example 31 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenethylpyridin-2(1H)-onehydrochloride a) (E)-2-Methoxy-4-styrylpyridine

4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronicacid (4.3 g, 30 mmol), K₂CO₃ (4.0 g, 30 mmol) and PdCl₂(dppf) (400 mg,0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. Theflask was flushed with nitrogen and the mixture was heated to 90° C. for30 min. Upon cooling, the mixture was diluted with methylene chlorideand washed with 5% lithium chloride solution (5×), dried, concentrated,and the residue was purified by flash column chromatography (silica gel,hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound(1.93 g, 93%) as an orange oil: ¹H NMR (300 MHz, CDCl₃) δ 8.12 (d, J=5.2Hz, 1H), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s,1H), 3.95 (s, 3H).

b) 2-Methoxy-4-phenethylpyridine

(E)-2-Methoxy-4-styrylpyridine (22.15 g, 104.8 mmol) was dissolved inMeOH (400 mL) and degassed with a nitrogen stream for 10 minutes.Palladium on charcoal (10%, wet, 5 g) was added and the reaction mixturewas stirred under an atmosphere of hydrogen for 24 h. The reactionmixture was degassed again, and the catalyst was removed by filtration.Concentration of the filtrate provided the title compound (22 g, 98%) asa green oil: ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=5.3 Hz, 1H), 7.29-7.24(m, 2H), 7.21-7.15 (m, 3H), 6.69-6.67 (m, 1H), 6.54 (s, 1H), 3.91 (s,3H), 2.91-2.89 (m, 2H), 2.87-2.84 (m, 2H).

c) 4-Phenethylpyridin-2(1H)-one

2-Methoxy-4-phenethylpyridine (22.0 g, 102 mmol) was stirred inconcentrated hydrochloric acid (200 mL) at 120° C. for 18 h and thenconcentrated. The residue was dissolved in MeOH (100 mL) and made basicwith aqueous 6 N NaOH and re-concentrated until most of the solvent hadbeen removed. The solids were filtered off, washed with water and driedunder vacuum to provide the title compound (21.3 g, 95%) as a beigesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.31 (br s, 1H), 7.28-7.21 (m, 5H),7.17 (t, J=7.1 Hz, 1H), 6.10-6.08 (m, 2H), 2.85-2.82 (m, 2H), 2.70-2.67(m, 2H).

d)1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenethylpyridin-2(1H)-onehydrochloride

4-Phenethylpyridin-2(1H)-one (82 mg, 0.41 mmol) and7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (115 mg,0.412 mmol) were reacted following the procedure for Example 30 (step g)to provide the title compound (54 mg, 30%) as a yellow solid: mp299-304° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.67-7.64 (m, 2H), 7.51 (d, J=1.8Hz, 1H), 7.30-7.24 (m, 4H), 7.20-7.17 (m, 1H), 7.08 (dd, J=8.4, 1.9 Hz,1H), 6.56 (dd, J=6.9, 1.9 Hz, 1H), 6.53 (s, 1H), 4.85 (m, 1H), 4.49 (d,J=15.3 Hz, 1H), 3.89-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.50 (m, 1H),3.21-3.19 (m, 2H), 3.16 (s, 3H), 3.02-2.99 (m, 2H), 2.96-2.93 (m, 2H);ESI MS m/z 398 [M+H]⁺; HPLC (Method B) 98.1% (AUC), t_(R)=13.5 min.

Example 32 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-onehydrochloride a) 4-(4-(Trifluoromethyl)benzyloxy)pyridine 1-oxide

4-Trifluoromethylbenzylalcohol (4.2 g, 23 mmol) was dissolved in DMF (20mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) wasadded. After stirring for 30 minutes, 4-chloropyridine-N-oxide (1.5 g,11.5 mmol) was added and the reaction mixture was heated for 1 h at 120°C. Upon cooling the mixture was diluted with methylene chloride andwashed with 5% lithium chloride solution (5×), dried and concentrated.Purification by flash column chromatography (40 g ISCO column elutingwith methylene chloride and a methanol/ammonia mixture (10:1); gradient100% methylene chloride to 90% methylene chloride over 30 min at 40mL/min) provided the title compound (0.6 g, 19%) as a yellow solid: ¹HNMR (300 MHz, CDCl₃) δ 8.14 (d, J=7.8 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H),7.52 (d, J=8.1 Hz, 2H), 6.86 (d, J=7.8 Hz, 2H), 5.15 (s, 2H).

b) 4-(4-(Trifluoromethyl)benzyloxy)pyridin-2(1H)-one

4-(4-(Trifluoromethyl)benzyloxy)pyridine 1-oxide (600 mg, 2.22 mmol) washeated to 140° C. in acetic anhydride (20 mL) for 2 h. The mixture wasconcentrated and then heated at 80° C. for 1 h in a mixture of MeOH (10mL) and aqueous 1 N NaOH (10mL). The resultant black solution wasconcentrated to a volume of 10 mL and extracted with CHCl₃/EtOH (3:1).The organic layer was removed and concentrated to provide the titlecompound (550 mg, 91%) as a tan solid: ¹H NMR (300 MHz, CD₃OD) δ7.70-7.60 (m, 4H), 7.41 (d, J=7.0 Hz, 1H), 6.17 (dd, J=7.0, 2.5 Hz, 1H),5.96 (d, J=2.4 Hz, 1H), 5.18 (s, 2H).

c)1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-onehydrochloride

4-(4-(Trifluoromethyl)benzyloxy)pyridin-2(1H)-one (100 mg, 0.37 mmol)and 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (103mg, 0.47 mmol) were reacted following the procedure for Example 30 (stepg) to provide the title compound (67 mg, 36%) as a light-brown solid: mp280-285° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.78-7.73 (m, 3H), 7.69-7.64 (m,3H), 7.52 (d, J=1.8 Hz, 1H), 7.18-7.08 (m, 1H), 6.55-6.52 (m, 1H), 6.28(d, J=2.6 Hz, 1H), 5.35 (s, 2H), 4.82-4.80 (m, 1H), 4.50 (d, J=15.4 Hz,1H), 3.89-3.85 (m, 1H), 3.73 (s, 3H), 3.55-3.50 (m, 1H), 3.22-3.16 (m,5H); ESI MS m/z 468 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=14.4 min.

Example 33 Preparation of4-(4-Chlorobenzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(4-Chlorobenzyloxy)pyridine 1-oxide

Beilstein Registry Number 7707045

4-Chlorobenzylalcohol (5.0 g, 35 mmol) was dissolved in DMF (25 mL) andNaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added.After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.27 g, 17.5mmol) was added and the reaction mixture was heated for 1 h at 120° C.Upon cooling, the mixture was diluted with methylene chloride and washedwith 5% lithium chloride solution (5×), dried and concentrated.Purification by flash column chromatography (12 g ISCO column elutingwith methylene chloride and a methanol/ammonia mixture (10:1); gradient100% methylene chloride to 90% methylene chloride over 30 min at 25mL/min) provided the title compound (1.9 g, 47%) as an orange solid: ¹HNMR (300 MHz, CDCl₃) δ 8.11 (d, J=7.7 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H),7.34 (d, J=8.6 Hz, 2H), 6.86 (d, J=7.7 Hz, 2H), 5.06 (s, 2H).

b) 4-(4-Chlorobenzyloxy)pyridin-2(1H)-one

Beilstein Registry Number 7707762

4-(4-Chlorobenzyloxy)pyridine 1-oxide (1.95 g, 8.24 mmol) was reactedaccording to the procedure of Example 32 (step b), and the crude productwas purified by flash column chromatography (40 g ISCO column elutingwith methylene chloride and a methanol/ammonia mixture (10:1); gradient100% methylene chloride to 90% methylene chloride over 30 min at 40mL/min) to provide the title compound (1.0 g, 51%) as a yellow solid: ¹HNMR (500 MHz, CDCl₃) δ 12.70 (br s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.33(d, J=8.5 Hz, 2H), 7.22 (d, J=7.3 Hz, 1H), 6.02 (dd, J=7.3, 2.5 Hz, 1H),5.93 (d, J=2.5 Hz, 1H), 4.98 (s, 2H).

c)4-(4-Chlorobenzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

4-(4-Chlorobenzyloxy)pyridin-2(1H)-one (82 mg, 0.34 mmol) and7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (97 mg,0.34 mmol) were reacted following the procedure for Example 30 (step g)to provide the title compound (28 mg, 17%) as a yellow solid: mp290-296° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.83 (d, J=7.6 Hz, 1H), 7.68 (d,J=8.3 Hz, 1H), 7.50-7.46 (m, 3H), 7.44-7.42 (m, 2H), 7.08 (dd, J=8.3,1.8 Hz, 1H), 6.41 (dd, J=7.6, 2.6 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.21(s, 2H), 4.86-4.84 (m, 1H), 4.49 (d, J=15.4 Hz, 1H), 3.88-3.84 (m, 1H),3.72 (s, 3H), 3.55-3.50 (m, 1H), 3.21-3.16 (m, 5H); ESI MS m/z 434[M+H]; HPLC (Method B) 98.6% (AUC), t_(R)=14.0 min.

Example 34 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride a) 4-(Pyridin-2-ylmethoxy)pyridine 1-oxide

2-Pyridylbenzylalcohol (1.67 g, 15.3 mmol) was dissolved in 1,4-dioxane(25 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol)was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.27g, 17.5 mmol) was added and the reaction mixture was heated for 1 h at120° C. Upon cooling, the mixture was purified by flash columnchromatography (40 g ISCO column eluting with methylene chloride and amethanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90%methylene chloride over 30 min at 40 mL/min) to provide the titlecompound (600 mg, 38%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ8.62-8.61 (m, 1H), 8.13-8.10 (m, 2H), 7.74 (overlapping ddd, J=7.8, 1.4Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.30 (d, J=4.8 Hz, 1H), 6.92-6.89 (m,2H), 5.23 (s, 2H).

b) 4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one

4-(Pyridin-2-ylmethoxy)pyridine 1-oxide (9.0 g, 45 mmol) was heated to140° C. in acetic anhydride (100 mL) for 2 h. The solution wasconcentrated and then heated at 80° C. for 1 h in a mixture of MeOH (50mL) and H₂O (50 mL). The resultant black solution was concentrated andthe residue was dissolved in hot i-PrOH (40 ml). Et₂O (250 mL) was addedand the mixture was placed in the freezer for 16 h. The solid wasfiltered off to provide the title compound (1.9 g, 21%) as a brownsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.13 (br s, 1H), 8.58 (d, J=4.7 Hz,1H), 7.85 (overlapping ddd, J=7.9, 1.6 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H),7.38-7.34 (m, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.96 (dd, J=7.3, 2.5 Hz, 1H),5.76 (d, J=3.4 Hz, 1H), 5.12 (s, 2H).

c)1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride

4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (109 mg, 0.539 mmol) and7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (97 mg,0.34 mmol) were reacted following the procedure for Example 30 (step g)to provide the title compound (28 mg, 11%) as a yellow solid: mp160-175° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.90 (dd, J=5.8, 1.8 Hz, 1H),8.65 (overlapping ddd, J=7.9, 1.6 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.07(overlapping dd, J=6.4 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.65 (d, J=6.4Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 7.07 (dd, J=6.8, 1.8 Hz, 1H), 6.63 (dd,J=7.6, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 5.59 (s, 2H), 4.80 (m, 1H),4.50 (d, J=15.3 Hz, 1H), 3.88-3.85 (m, 1H), 3.73 (s, 3H), 3.55-3.50 (m,1H), 3.21-3.16 (m, 5H); ESI MS m/z 401 [M+H]⁺; HPLC (Method B)>99%(AUC), t_(R)=9.3 min.

Example 35 Preparation of4-((5-Chloropyridin-2-yl)methoxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) 4-((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide

5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according toExample 34 (step a) to provide the title compound (2.2 g, 40%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 8.58 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.7Hz, 2H), 7.74 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d,J=7.7 Hz, 2H), 5.20 (s, 2H).

5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according toExample 34 (step a) to provide the title compound (2.2 g, 40%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 8.58 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.7Hz, 2H), 7.76-7.72 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90(d, J=7.7 Hz, 2H), 5.20 (s, 2H).

b) 4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one

4-((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide (2.2 g, 9.2 mmol) wasreacted according to Example 34 (step b) to provide the title compound(1.52 g, 69%) as a tan solid: ¹H NMR (500 MHz, CD₃OD) δ 8.56 (d, J=2.3Hz, 1H), 7.91-7.89 (dd, J=8.4, 2.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.34(d, J=8.3 Hz, 1H), 6.21-6.19 (dd, J=7.2, 2.5 Hz, 1H), 5.97 (d, J=2.4 Hz,1H), 5.18 (s, 2H).

c) tert-Butyl7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (259 mg, 1.09 mmol)and tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(400 mg, 1.1 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (145 mg, 25%) as a yellow solid:ESI MS m/z 521 [M+H]⁺.

d)4-((5-Chloropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(145 mg, 0.278 mmol) was deprotected and converted to thedihydrochloride salt according to the procedure of Example 30 (steps eand g) to provide the title compound (114 mg, 94%) as a yellow solid: mp275-280° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.61 (s, 1H), 7.77 (dd, J=8.3,3.8 Hz, 1H), 7.64-7.62 (m, 3H), 7.47 (d, J=1.6 Hz, 1H), 7.03 (dd, J=8.4,1.8 Hz, 1H), 6.37 (dd, J=7.6, 3.8 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 5.28(s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J=6.1 Hz, 2H), 3.12 (t,J=6.0 Hz, 2H); ESI MS m/z 421 [M+H]⁺; HPLC (Method B) 98.5% (AUC),t_(R)=12.1 min

Example 36 Preparation of4-((5-Chloropyridin-2-yl)methoxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

4-((5-Chloropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(80 mg, 0.19 mmol) was dissolved a mixture of MeOH (3 mL) and CH₂Cl₂ (1mL) and formaldehyde (9.0 mg, 0.29 mmol, 37% aqueous solution) wasadded. After stirring for 45 minutes, NaBH(OAc)₃ (80 mg, 0.38 mmol) wasadded and the reaction mixture was stirred for a further 10 minutes. Themixture was diluted with CH₂Cl₂, washed with saturated Na₂CO₃ solutionand concentrated to provide the free base. Conversion to thedihydrochloride salt using the procedure of Example 30 (step g) providedthe title compound (83 mg, 86%) as an orange solid: mp 202-210° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.68 (br s, 1H), 8.05 (dd, J=8.0, 2.4 Hz, 1H),7.76 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H),7.51 (d, J=1.6 Hz, 1H), 7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.53 (dd, J=7.6,1.7 Hz, 1H), 6.28 (d, J=1.6 Hz, 1H), 5.36 (s, 2H), 4.85-4.80 (m, 1H),4.49 (d, J=15.3 Hz, 1H), 3.89-3.84 (m, 1H), 3.72 (s, 3H), 3.53-3.47 (m,1H), 3.22-3.19 (m, 2H), 3.16 (s, 3H); ESI MS m/z 435 [M+H]⁺; HPLC(Method B) 97.8% (AUC), t_(R)=12.2 min.

Example 37 Preparation of4-(4-Chlorophenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

4-(4-Chlorophenyl)pyridin-2(1H)-one (80 mg, 0.33 mmol) and7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (49 mg,0.33 mmol) were reacted following the procedure of Example 30 (step g)to provide the title compound (28 mg, 19%) as a yellow-green solid: mp316-323° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.0 (br s, 1H), 7.83 (dd,J=6.8, 1.9 Hz, 2H), 7.76 (d, J=7.1 Hz, 1H), 7.62-7.57 (m, 4H), 7.07 (dd,J=8.3, 1.8 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.69 (dd, J=7.2, 2.1 Hz,1H), 4.79 (d, J=15.2 Hz, 1H), 4.44 (dd, J=15.2, 6.0 Hz, 1H), 3.74-3.68(m, 4H), 3.48-3.38 (m, 1H), 3.10-2.99 (m, 5H); ESI MS m/z 404 [M+H]⁺;HPLC (Method B)>99% (AUC), t_(R)=13.5 min.

Example 38 Preparation of4-(4-Chlorophenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(4-Chlorophenyl)pyridin-2(1H)-one (74 mg, 0.32 mmol) and tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(74 mg, 0.36 mmol) were coupled following the procedure of Example 30(step g) to provide the title compound (85 mg, 54%) as a yellow solid:¹H NMR (300 MHz, CD₃OD) δ 7.58-7.55 (m, 3H), 7.51-7.44 (m, 3H), 7.35 (s,1H), 7.07 (dd, J=8.2, 1.6 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.47 (dd,J=7.1, 1.8 Hz, 1H), 4.65 (br m, 2H), 3.75 (br m, 2H), 3.64 (s, 3H), 2.81(br m, 2H), 1.52 (s, 9H).

b)4-(4-Chlorophenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(85 mg, 0.17 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (38 mg, 52%) as a yellow solid: mp 310-315° C.; ¹HNMR (500 MHz, CD₃OD) δ 7.78-7.75 (m, 3H), 7.67 (d, J=8.3 Hz, 1H),7.55-7.53 (m, 3H), 7.13 (dd, J=8.3, 1.8 Hz, 1H), 6.91 (d, J=1.9 Hz, 1H),6.84 (dd, J=7.1, 2.0 Hz, 1H), 4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J=6.0Hz, 2H), 3.14 (t, J=6.0 Hz, 2H); ESI MS m/z 390 [M+H]⁺; HPLC (MethodB)>99% (AUC), t_(R)=13.6 min.

Example 39 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride hydrochloride a) 4-(4-(Trifluoromethyl)phenyl)pyridine1-oxide

4-Chloropyridine-N-oxide (3.0 g, 23 mmol),4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K₂CO₃ (4.8 g,35 mmol) and PdCl₂(dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40mL) under vacuum for 30 min. The flask was flushed with nitrogen and themixture was heated to 80° C. for 10 min. Upon cooling, the mixture wasdiluted with methylene chloride and washed with 5% lithium chloridesolution (5×), dried, concentrated and the residue was purified by flashcolumn chromatography (40 g ISCO column eluting with methylene chlorideand a methanol/ammonia mixture (10:1); gradient 100% methylene chlorideto 80% methylene chloride over 30 min at 40 mL/min) to provide the titlecompound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]⁺.

b) 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one

4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9 mmol) wasreacted according to the procedure of Example 32 (step b) to provide thetitle compound (1.26 g, 66%) as a brown solid: ¹H NMR (300 MHz, CD₃OD) δ7.80-7.74 (br m, 5H), 6.85-6.66 (br m, 2H).

c) tert-Butyl9-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (86 mg, 0.36 mmol) andtert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(120 mg, 0.32 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (97 mg, 58%) as a yellow solid:¹H NMR (300 MHz, CDCl₃) δ 7.74 (s, 4H), 7.58-7.52 (m, 2H), 7.36 (s, 1H),7.08 (dd, J=8.2, 1.8 Hz, 1H), 6.92 (d, J=1.9 Hz, 1H), 6.50 (dd, J=7.2,2.0 Hz, 1H), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.81 (br m,2H), 1.52 (s, 9H).

d)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

tert-Butyl9-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(97 mg, 0.19 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (53 mg, 62%) as a yellow solid: mp 316-321° C.; ¹HNMR (300 MHz, CD₃OD) δ 7.97 (d, J=8.1 Hz, 2H), 7.87-7.80 (m, 3H), 7.68(d, J=8.2 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.14 (dd, J=8.3, 1.8 Hz, 1H),6.96 (d, J=1.8 Hz, 1H), 6.87 (dd, J=7.2, 1.8 Hz, 1H), 4.56 (s, 2H), 3.74(s, 3H), 3.61 (t, J=6.0 Hz, 2H), 3.14 (t, J=6.0 Hz, 2H); ESI MS m/z 424[M+H]⁺; HPLC (Method B) 96.3% (AUC), t_(R)=14.0 min.

Example 40 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (100 mg, 0.42 mmol) and7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (117 mg,0.419 mmol) were reacted following the procedure of Example 30 (step g)to provide the title compound (70 mg, 35%) as a yellow-brown solid: mp294-299° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.96 (d, J=8.2 Hz, 2H), 7.85-7.83(m, 3H), 7.68 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.16 (dd,J=8.3, 1.7 Hz, 1H), 6.98 (d, J=1.8 Hz, 1H), 6.90 (dd, J=7.1, 1.9 Hz,1H), 4.87-4.86 (m, 1H), 4.51 (d, J=15.3 Hz, 1H), 3.90-3.86 (m, 1H), 3.74(s, 3H), 3.57-3.51 (m, 1H), 3.23-3.20 (m, 2H), 3.17 (s, 3H); ESI MS m/z438 [M+H]⁺; HPLC (Method B) 95.6% (AUC), t_(R)=14.1 min.

Example 41 Preparation of4-(2,4-Dichlorophenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(2,4-Dichlorophenyl)pyridine 1-oxide

4-Chloropyridine-N-oxide (1.5 g, 12 mmol), 2,4-dichlorophenylboronicacid (5.4 g, 29 mmol) were reacted according to the procedure of Example39 (step a) to provide the title compound (1.40 g, 50%) as a grey solid:¹H NMR (500 MHz, CD₃OD) δ 8.26 (d, J=6.9 Hz, 2H), 7.53 (d, J=2.0 Hz,1H), 7.37-7.35 (m, 3H), 7.29 (d, J=8.3 Hz, 1H).

b) 4-(2,4-Dichlorophenyl)pyridin-2(1H)-one

4-(2,4-Dichlorophenyl)pyridine 1-oxide (1.4 g, 5.8 mmol) was reactedaccording to the procedure of Example 32 (step b) to provide the titlecompound (0.95 g, 67%) as a brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.75 (br m, 1H), 7.75 (s, 1H), 7.51-7.46 (m, 3H), 6.31-6.22 (m, 2H).

c)4-(2,4-Dichlorophenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

4-(2,4-Dichlorophenyl)pyridin-2(1H)-one (103 mg, 0.429 mmol) and7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (120 mg,0.43 mmol) were reacted following the procedure of Example 30 (step g)to provide the title compound (44 mg, 21%) as a yellow solid: mp308-313° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.77 (d, J=7.0 Hz, 1H), 7.68 (d,J=8.4 Hz, 1H), 7.65 (overlapping dd, J=1.1 Hz, 1H), 7.58 (d, J=1.7 Hz,1H), 7.49 (s, 2H), 7.16 (dd, J=8.3, 1.8 Hz, 1H), 6.70 (d, J=1.5 Hz, 1H),6.62 (dd, J=7.0, 1.9 Hz, 1H), 4.86 (m, 1H), 4.50 (d, J=15.3 Hz, 1H),3.89-3.85 (m, 1H), 3.74 (s, 3H), 3.56-3.55 (m, 1H), 3.23-3.20 (m, 2H),3.16 (s, 3H); ESI MS m/z 438 [M+H]⁺; HPLC (Method B) 98.5% (AUC),t_(R)=14.3 min.

Example 42 Preparation of4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(Benzyloxy)pyridin-2(1H)-one (580 mg, 0.28 mmol) and tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(850 mg, 0.23 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (700 mg, 62%) as a green solid:¹H NMR (500 MHz, CDCl₃) δ 7.52 (d, J=8.2 Hz, 1H), 7.44-7.39 (m, 4H),7.38-7.35 (m, 1H), 7.31-7.28 (m, 2H), 7.01 (dd, J=8.3, 1.8 Hz, 1H), 6.09(d, J=2.6 Hz, 1H), 6.04 (dd, J=7.6, 2.6 Hz, 1H), 5.05 (s, 2H), 4.64 (brm, 2H), 3.74 (br m, 2H), 3.62 (s, 3H), 2.79 (br m, 2H), 1.47 (s, 9H).

b)4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(700 mg, 1.44 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (530 mg, 83%) as a yellow solid: mp 251-257° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 9.71 (br s, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.54(d, J=8.3 Hz, 1H), 7.50-7.47 (m, 3H), 7.44-7.41 (m, 2H), 7.38-7.37 (m,1H), 6.99 (dd, J=8.3, 1.8 Hz, 1H), 6.11 (dd, J=7.6, 2.8 Hz, 1H), 5.97(d, J=2.6 Hz, 1H), 5.15 (s, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.42-3.41(m, 2H), 2.98-2.97 (m, 2H); ESI MS m/z 386 [M+H]⁺; HPLC (Method B)>99%(AUC), t_(R)=12.9 min.

Example 43 Preparation of4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(70 mg, 0.18 mmol), 2-iodoethanol (156 mg, 0.907 mmol) and K₂CO₃ (250mg, 1.8 mmol) were combined in DMF (3 mL) and heated to 80° C. for 1 h.Upon cooling, the product was purified by preparative HPLC and thenflash column chromatography (12 g ISCO column eluting with methylenechloride and a methanol/ammonia mixture (10:1); gradient 100% methylenechloride to 90% methylene chloride over 30 min at 25 mL/min) to providethe free-base. This was converted to the hydrochloride salt as ofExample 30 (step g) to provide the title compound (14.8 mg, 18%) as ayellow solid: ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J=8.4 Hz, 1H), 7.61 (d,J=7.5 Hz, 1H), 7.47-7.46 (m, 3H), 7.42-7.39 (m, 2H), 7.36 (d, J=7.1 Hz,1H), 7.06 (dd, J=8.3, 1.8 Hz, 1H), 6.33 (dd, J=7.6, 2.6 Hz, 1H), 6.15(d, J=2.6 Hz, 1H), 5.19 (s, 2H), 4.81-4.79 (m, 1H), 4.59 (d, J=15.3 Hz,1H), 4.01 (t, J=5.1 Hz, 2H), 3.97-3.94 (m, 1H), 3.73 (s, 3H), 3.58-3.50(m, 3H), 3.21-3.16 (m, 2H); ESI MS m/z 430 [M+H]⁺; HPLC (Method B) 97.2%(AUC), t_(R)=12.8 min.

Example 44 Preparation of4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a)4-(Benzyloxy)-1-(2-(2-chloroacetyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (100 mg, 0.23 mmol) was stirred in a mixture of CH₂Cl₂ (2mL) and saturated NaHCO₃ solution (2 mL) and chloroacetyl chloride (32mg, 0.28 mmol) was added. After 1.5 h, the organic layer was removed andconcentrated to provide the title compound (120 mg, 100%) as a yellowoil: ESI MS m/z 462 [M+H]⁺.

b)4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

4-(Benzyloxy)-1-(2-(2-chloroacetyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(120 mg. 0.23 mmol), pyrrolidine (85 mg, 1.2 mmol) and K₂CO₃ (331 mg,2.39 mmol) were combined in DMF (3 mL) and heated to 80° C. for 1 h.Upon cooling, the mixture was diluted with methylene chloride and washedwith 5% lithium chloride solution (5×), dried over Na₂SO₄ andconcentrated. The residue was converted to the hydrochloride salt as ofExample 30 (step g) to provide the title compound (110 mg, 60%) as ayellow solid: mp 190-200° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.86 (d, J=7.5Hz, 1H), 7.62 (dd, J=8.2, 2.7 Hz, 1H), 7.51-7.50 (m, 3H), 7.46-7.43 (m,2H), 7.41-7.40 (m, 1H), 7.08-7.06 (m, 1H), 6.63 (dd, J=7.8, 2.6 Hz, 1H),6.40 (d, J=1.4 Hz, 1H), 5.31 (s, 2H), 4.93 (s, 1.3H), 4.77 (s, 0.7H),4.56-4.55 (m, 2H), 4.04-4.02 (m, 0.6H), 3.81-3.78 (m, 3.4H), 3.76 (s,3H), 3.24-3.19 (m, 2H), 2.79-2.97 (m, 1.3H), 2.92-2.85 (m, 0.7H),2.22-2.19 (m, 2H), 2.11-2.19 (m, 2H); ESI MS m/z 497 [M+H]⁺; HPLC(Method B)>99% (AUC), t_(R)=13.7 min.

Example 45 Preparation of(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) (S)-tert-Butyl2-(7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)pyrrolidine-1-carboxylate

4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (50 mg, 0.12 mmol) was stirred in DMF (1 mL) and saturatedBoc-L-proline (30 mg, 0.14 mmol), HATU (68 mg, 0.18 mmol) and Et₃N (36mg, 0.36 mmol) were added. After 16 h, the mixture was diluted withmethylene chloride and washed with 5% lithium chloride solution (5×),dried over Na₂SO₄ and concentrated. The residue was purified by flashcolumn chromatography (12 g ISCO column eluting with methylene chlorideand a methanol/ammonia mixture (10:1); gradient 100% methylene chlorideto 90% methylene chloride over 30 min at 25 mL/min) to provide the titlecompound (55 mg, 78%) as a colorless oil: ESI MS m/z 583 [M+H]⁺.

b)(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

(S)-tert-Butyl2-(7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)pyrrolidine-1-carboxylate(55 mg, 0.094 mmol) was stirred in a mixture of MeOH (2 mL) and 2 N HClin Et₂O (8 mL) for 5 h. The reaction mixture was concentrated to providethe title compound (42 mg, 85%) as a yellow-green solid: mp 220-226° C.;¹H NMR (500 MHz, CD₃OD) δ 7.79 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (d, J=8.3Hz, 1H), 7.49-7.46 (m, 3H), 7.44-7.46 (m, 2H), 7.39-7.36 (m, 1H), 7.04(dd, J=8.3, 1.6 Hz, 1H), 6.57-6.55 (m, 1H), 6.34 (d, J=2.5 Hz, 1H), 5.27(s, 2H), 4.96-4.87 (m, 2H), 3.90-8.86 (m, 2H), 3.77 (s, 3H), 3.48-3.34(m, 3H), 3.00-2.86 (m, 2H), 2.67-2.61 (m, 1H), 2.17-2.02 (m, 3H); ESI MSm/z 483 [M+H]⁺; HPLC (Method B) 95.5% (AUC), t_(R)=13.5 min.

Example 46 Preparation of4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)pyridin-2(1H)-onehydrochloride a) 2-(5-Bromo-1H-indol-3-yl)ethanamine

Beilstein Registry Number 143491

4-Bromophenylhydrazine hydrochloride (20.0 g, 85.8 mmol) was reactedaccording to the procedure of Mascal et al. (Rinehart, Kenneth L.;Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy; Mascal, Mark; etal. J. Am. Chem. Soc. 1987, 109, 3378-3387) to provide the titlecompound (5.2 g, 25%) as an orange solid: ESI MS m/z 239 [M+H]⁺.

b) 6-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Beilstein Registry Number 911238

2-(5-Bromo-1H-indol-3-yl)ethanamine (5.2 g, 22 mmol) was reactedaccording to the procedure of Mascal et al. (Rinehart, Kenneth L.;Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy; Mascal, Mark; etal. J. Am. Chem. Soc. 1987, 109, 3378-3387) to provide the titlecompound (2.6 g, 48%) as an orange solid: ESI MS m/z 251 [M+H]⁺.

c) tert-Butyl6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

6-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2.6 g, 10 mmol) wassuspended in CH₂Cl₂ (50 mL) and THF (7.5 mL) and Boc₂O (2.3 g, 11 mmol)was added. After 2.5 h, the mixture was concentrated. Purification byflash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to70:30) gave the title compound (1.15 g, 30%) as an orange powder: ¹H NMR(300 MHz, CDCl₃) δ 7.59 (s, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.5Hz, 1H), 4.68-4.59 (br m, 2H), 3.80-3.70 (br m, 2H), 2.78-2.71 (br m,2H), 1.50 (s, 9H).

d) tert-Butyl6-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

tert-Butyl 6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(1.15 g, 3.26 mmol) was dissolved in DMF (20 mL) and sodium hydride (60%weight dispersion in mineral oil, 196 mg, 4.89 mmol) was added. After 1h, methyl iodide (0.30 mL, 4.9 mmol) was added and the reaction mixturewas stirred for a further 30 min. The mixture was diluted with methylenechloride and washed with 5% lithium chloride solution (5×), dried overNa₂SO₄ and concentrated. Purification by flash column chromatography(silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the titlecompound (740 mg, 36%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.58(s, 1H), 7.24 (d overlapped by solvent, J=8.5, 1H), 7.14 (d, J=8.5, 1H),4.67-4.53 (br m, 2H), 3.79-3.67 (br m, 2H), 3.60 (s, 3H), 2.78-2.66 (brm, 2H), 1.51 (s, 9H).

e) tert-Butyl6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

A solution oftert-Butyl-6-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(750 mg, 2.03 mmol) in DMSO (10 mL) was stirred under nitrogen andtreated sequentially with 4-(benzyloxy)pyridin-2(1H)-one (448 mg, 2.23mmol), 8-hydroxyquinoline (44 mg, 0.305 mmol), CuI (58 mg, 0.305 mmol)and K₂CO₃ (308 mg, 2.23 mmol). After stirring overnight at 130° C., themixture was allowed to cool to room temperature and a mixture of MeOHand NH₄OH (10:1, 10 mL) was added. After stirring for 15 min, themixture was diluted with CH₂Cl₂, washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness. Purification by flash columnchromatography (40 g ISCO column eluting with a 1:1 ethylacetate/hexanesand a methanol/ammonia mixture (10:1); gradient 100% 1:1ethylacetate/hexanes to 90% 1:1 ethylacetate/hexanes/10%methanol/ammonia mixture (10:1) over 30 min at 25 mL/min) provided thetitle compound (340 mg, 33%) as a yellow solid; ¹H NMR (500 MHz, CDCl₃)δ 7.50-7.36 (m, 8H), 7.13 (d, J=7.8, Hz, 1H), 6.09 (d, J=2.6 Hz, 1H),6.03 (dd, J=7.5, 2.7 Hz, 1H), 5.05 (s, 2H), 4.65 (br s, 2H), 3.73 (br s,2H), 3.66 (s, 3H), 2.77 (br s, 2H), 1.51 (s, 9H).

f)4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(0.340 g, 0.70 mmol) was dissolved in MeOH (5 mL) and 2 N HCl in ether(15 mL) was added. After stirring for 1 h, the liquid was decanted offand the resultant solid was filtered and washed with ether (3×). Thisprovided the title compound (267 mg, 98%) as a light yellow solid: mp290-300° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.66 (d, J=7.5 Hz, 1H), 7.57-7.52(m, 2H), 7.46 (d, J=7.7 Hz, 2H), 7.41 (overlapping dd, J=7.3 Hz, 2H),7.36 (d, J=7.5 Hz, 1H), 7.19 (dd, J=8.6, 2.0 Hz, 1H), 6.42 (dd, J=7.5,2.7 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.55 (s, 2H), 3.75(s, 3H), 3.58 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H); ESI MS m/z 386[M+H]⁺; HPLC (Method B) 98.8% (AUC), t_(R)=12.8 min.

Example 47 Preparation of4-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pydido[3,4-b]indol-6-yl)pyridine-2(1H)-onehydrochloride (126 mg, 0.325 mmol) was dissolved in MeOH (2 mL) andCH₂Cl₂ (0.5 mL) and formaldehyde (0.036 mL, 37% aqueous solution) wasadded. After stirring for 1 h, NaBH(OAc)₃ (138 mg, 0.651 mmol) was addedand the mixture was stirred for a further 40 min. The mixture wasdiluted with methylene chloride (50 mL), washed with saturated Na₂CO₃solution, concentrated and purified by flash column chromatography (12 gISCO column eluting with methylene chloride and a methanol/ammoniamixture (10:1); gradient 100% methylene chloride to 85% methylenechloride over 30 min at 40 mL/min), and further purified by preparativeHPLC to provide the title compound (55.5 mg, 43%) as a white powder: mp260-270° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.56-7.53 (m, 2H), 7.51 (d,J=1.8, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.41 (overlapping dd, J=7.4 Hz, 2H),7.36 (d, J=7.2 Hz, 1H), 7.19 (dd, J=8.6, 2.0 Hz, 1H), 6.27 (dd, J=7.6,2.7 Hz, 1H), 6.11 (d, J=2.6 Hz, 1H), 5.18 (s, 2H), 4.64 (br s, 2H), 3.75(s, 3H), 3.67 (br s, 2H), 3.18-3.13 (m, 5H); ESI MS m/z 400 [M+H]⁺; HPLC(Method B)>99% (AUC), t_(R)=12.9 min.

Example 48 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride a) 2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine

2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500mg, 1.81 mmol) were reacted according to Example 31 (step a) to providethe title compound (337 mg, 62%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz,1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H),3.52 (s, 3H).

b) 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (337 mg, 1.32 mmol) wasreacted reacted according to Example 31 (step c) to provide the titlecompound (289 mg, 89%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.08 (s, 1H) 9.10 (s, 1H), 8.35 (dd, J=8.4, 2.1 Hz, 1H), 8.25 (d, J=8.3Hz, 1H), 7.53 (d, J=6.8, 1H), 7.09 (d, J=1.3 Hz, 1H), 6.90 (dd, J=6.8,1.6 Hz, 1H).

c) tert-Butyl5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (100 mg, 0.41 mmol)and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(152 mg, 0.416 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (83 mg, 38%) as a green solid: ¹HNMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.06 (dd, J=8.3, 2.1 Hz, 1H), 7.91(d, J=8.3 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.37(d, J=1.6 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.03(dd, J=7.1, 1.8 Hz, 1H), 4.66 (s, 2H), 3.85 (br m, 2H), 3.66 (s, 3H),2.84 (br m, 2H), 1.51 (s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(83 mg, 0.16 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (51 mg, 78%) as a yellow solid: mp 320-330° C.; ¹HNMR (500 MHz, CD₃OD) δ 9.06 (s, 1H), 8.28 (dd, J=8.4, 2.1 Hz, 1H), 8.23(d, J=8.2 Hz, 1H), 7.87 (d, J=7.1 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.58(d, J=1.6 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.29 (dd, J=Hz, 1H), 7.17(dd, J=8.3, 1.8 Hz, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 3.69 (t, J=6.0 Hz,2H), 3.22 (t, J=Hz, 2H); ESI MS m/z 425 [M+H]⁺; HPLC (Method B)>99%(AUC), t_(R)=12.5 min.

Example 49 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide

5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) and4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) were reacted according toExample 34 (step a) to provide the title compound (1.76 g, 50%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H),7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).

b) 4-((5-Fluoroyridin-2-yl)methoxy)pyridin-2(1H)-one

4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol)was reacted according to Example 34 (step b) to provide the titlecompound (1.29 g, 73%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ11.12 (s, 1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (dt, J=8.7, 2.9 Hz, 1H),7.60 (dd, J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4,2.6 Hz, 1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).

c) tert-Butyl7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-((5-Fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (275 mg, 1.25 mmol)and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(456 mg, 1.25 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (420 mg, 66%) as a yellow solid:¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, J=2.1 Hz, 1H), 7.50 (m, 3H), 7.36 (d,J=7.8 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 6.11-6.08(m, 2H), 5.18 (s, 2H), 4.65 (s, 2H), 3.87 (t, J=5.3 Hz, 2H), 3.65 (s,3H), 2.84 (t, J=4.2 Hz, 2H), 1.60 (s, 9H).

d)4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(415 mg, 0.823 mmol) was deprotected and converted to thedihydrochloride according to procedure of Example 30 (steps e and g) toprovide the title compound (328 mg, 84%) as a white solid: mp 174-180°C.; ¹H NMR (500 MHz, CD₃OD) δ 8.70 (s, 1H), 8.00 (dt, J=8.4, 2.8 Hz,1H), 7.91-7.88 (m, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.11 (dd,J=8.3, 1.7 Hz, 1H), 6.69 (dd, J=7.5, 2.7 Hz, 1H), 6.45 (d, J=2.6 Hz,1H), 5.46 (s, 2H), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J=6.1 Hz, 2H),3.22 (t, J=6.1 Hz, 2H); ESI MS m/z 405 [M+H]⁺; HPLC (Method B) 95.5%(AUC), t_(R)=10.9 min.

Example 50 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride a) 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine

3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol) and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176mg, 0.749 mmol) were reacted according to Example 31 (step a) to providethe title compound (115 mg, 60%) as a white solid: ¹H NMR (500 MHz,CDCl₃) δ 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).

b) 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one

3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115 mg, 0.451mmol) was reacted according to Example 31 (step c) to provide the titlecompound (120 mg, quant) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ11.87 (s, 1H), 8.61 (d, J=8.9 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 7.62 (d,J=6.8 Hz, 1H), 7.19 (s, 1H), 7.01 (dd, J=6.8, 1.6 Hz, 1H).

c) tert-Butyl5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (60 mg, 0.25mmol) and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(90 mg, 0.25 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (60 mg, 46%) as a yellow solid:¹H NMR (500 MHz, CDCl₃) δ 8.10 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz,1H), 7.66 (d, J=7.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.38 (d, J=1.3 Hz,1H), 7.26-7.24 (m, 2H), 7.10 (d, J=7.8 Hz, 1H), 4.66 (s, 2H), 3.66 (t,J=3.3 Hz, 2H), 3.86 (s, 3H), 2.84 (t, J=3.3 Hz, 2H), 1.51 (s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(60 mg, 0.11 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (44 mg, 88%) as a yellow solid: mp 315-320° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.54 (d, J=8.8 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H),7.91 (d, J=7.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H),7.44 (d, J=1.5 Hz, 1H), 7.35 (dd, J=7.2, 1.9 Hz, 1H), 7.16 (dd, J=8.3,1.8 Hz, 1H), 4.50 (s, 2H), 3.77 (s, 3H), 3.69 (t, J=6.1 Hz, 2H), 3.22(t, J=6.0 Hz, 2H); ESI MS m/z 426 [M+H]⁺; HPLC (Method B) 95.9% (AUC),t_(R)=11.7 min.

Example 51 Preparation of4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (127 mg, 0.537 mmol)and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 1.1 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (113 mg, 40%) as a white solid:¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J=2.4 Hz, 1H), 7.73 (dd, J=8.4, 2.4Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.33 (d, J=7.5Hz, 1H), 7.29 (d, J=1.5 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.09 (dd,J=7.5, 2.7 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.64 (s, 2H),3.84 (t, J=5.4 Hz, 2H), 3.63 (s, 3H), 2.82 (t, J=5.4 Hz, 2H), 1.50 (s,9H).

b)4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(108 mg, 0.207 mmol) was deprotected and converted to thedihydrochloride salt according to the procedure of Example 30 (steps eand g) to provide the title compound (99 mg, 97%) as a white solid: mp290-320° C. dec; ¹H NMR (300 MHz, CD₃OD) δ 8.61 (d, J=2.1 Hz, 1H), 7.95(dd, J=8.4, 2.4 Hz, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H),7.47 (d, J=1.6 Hz, 1H), 7.05 (dd, J=8.3, 1.8 Hz, 1H), 6.36 (dd, J=7.6,2.2 Hz, 1H), 6.13 (d, J=2.6 Hz, 1H), 5.28 (s, 2H), 4.48 (s, 2H), 3.73(s, 3H), 3.67 (t, J=6.2 Hz, 2H), 3.02 (t, J=6.2 Hz, 2H); ESI MS m/z 421[M+H]⁺; HPLC (Method B) 98.2% (AUC), t_(R)=12.0 min.

Example 52 Preparation of4-((5-Chloropyridin-2-yl)methoxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(50 mg, 0.12 mmol) was reacted according to the procedure of Example 47to provide the free-base. Conversion to the dihydrochloride salt usingthe procedure of Example 30 (step g) provided the title compound (39 mg,64%) as a white solid: mp 278-282° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.60(d, J=2.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.61 (d, J=7.7 Hz, 2H), 7.57 (d,J=8.3 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 7.06 (dd, J=8.4, 1.7 Hz, 1H),6.34 (dd, J=7.6, 2.6 Hz, 1H), 6.12 (d, J=2.6 Hz, 1H), 5.27 (s, 2H), 4.75(d, J=14.2 Hz, 1H), 4.38 (d, J=14.1 Hz, 1H), 3.95-3.85 (m, 1H), 3.73 (s,3H), 3.63 (m, 1H), 3.31 (m overlapping with solvent, 2H), 3.13 (s, 3H);ESI MS m/z 435 [M+H]⁺; HPLC (Method B) 98.9% (AUC), t_(R)=12.1 min.

Example 53 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride a) tert-Butyl5-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (110 mg, 0.54 mmol) andtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.54 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (113 mg, 43%) as a yellow oil: ¹HNMR (300 MHz, CDCl₃) δ 8.63 (ddd, J=4.9, 1.6, 0.9 Hz, 1H), 7.75(overlapping ddd, J=7.6, 1.8 Hz, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.33 (d,J=7.5 Hz, 1H), 7.29 (d, J=1.4 Hz, 1H), 7.26 (m overlapping with solvent,1H), 7.01 (d, J=7.9 Hz, 1H), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.64 (s,2H), 3.84 (t, J=5.4 Hz, 2H), 3.62 (s, 3H), 2.82 (t, J=5.4 Hz, 2H), 1.52(s, 9H).

b)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(113 mg, 0.23 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (81 mg, 77%) as a white solid: mp 206-211° C.; ¹H NMR(300 MHz, CDCl₃) δ 8.88 (d, J=5.2 Hz, 1H), 8.59 (dd, J=7.9, 1.5 Hz, 1H),8.15 (d, J=8.0 Hz, 1H), 8.01 (overlapping dd, J=6.6 Hz, 1H), 7.69 (d,J=7.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.06 (dd,J=8.4, 1.8 Hz, 1H), 6.44 (dd, J=7.6, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz,1H), 5.57 (s, 2H), 4.48 (s, 2H), 3.74 (s, 3H), 3.68 (t, J=6.2 Hz, 2H),3.21 (t, J=6.2 Hz, 2H); ESI MS m/z 387 [M+H]⁺; HPLC (Method B) 98%(AUC), t_(R)=9.3 min.

Example 54 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one(45 mg, 0.116 mmol) was reacted according to the procedure of Example 47to provide the free-base. Conversion to the dihydrochloride salt usingthe procedure of Example 30 (step g) provided the title compound (54 mg,98%) as a white solid: mp 260-265° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.87(d, J=5.7 Hz, 1H), 8.58 (overlapping dd, J=8.2 Hz, 1H), 8.14 (d, J=7.9Hz, 1H), 8.00 (overlapping dd, J=6.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H),7.59 (d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.07 (dd, J=8.3, 1.7 Hz, 1H), 6.44(dd, J=7.5, 2.6 Hz, 1H), 6.20 (d, J=2.0 Hz, 1H), 5.56 (s, 2H), 4.76 (d,J=14.2 Hz, 1H), 4.40 (d, J=14.2 Hz, 1H), 3.91 (m, 1H), 3.74 (s, 3H),3.61 (m, 1H), 3.29-3.17 (m overlapping with solvent, 2H), 3.13 (s, 3H);ESI MS m/z 401 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=9.2 min.

Example 55 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride a) tert-Butyl9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (138 mg, 0.682 mmol) andtert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(250 mg, 0.68 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (170 mg, 51%) as a white foam: ¹HNMR (300 MHz, CDCl₃) δ 8.63 (d, J=4.1 Hz, 1H), 7.76 (overlapping ddd,J=7.7, 1.7 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.33(d, J=7.4 Hz, 1H), 7.29-7.26 (m overlapping with solvent, 2H), 7.01 (dd,J=8.2, 1.8 Hz, 1H), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.63 (s, 2H), 3.74(br s, 2H), 3.62 (s, 3H), 2.79 (s, 2H), 1.51 (s, 9H).

b)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride

tert-Butyl9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(167 mg, 0.34 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (124 mg, 79%) as a yellow solid: mp 226-231° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.89 (d, J=5.4 Hz, 1H), 8.61 (overlapping ddd,J=8.0, 1.6 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.02 (overlapping dd, J=6.6Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.47 (d, J=1.6Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz, 1H), 6.44 (dd, J=7.6, 2.7 Hz, 1H),6.21 (d, J=2.6 Hz, 1H), 5.57 (s, 2H), 4.56 (s, 2H), 3.73 (s, 3H), 3.60(t, J=6.0, 2H), 3.13 (t, J=6.0, 2H); ESI MS m/z 387 [M+H]⁺; HPLC (MethodB) 98.6% (AUC), t_(R)=9.2 min.

Example 56 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenethylpyridin-2(1H)-onedihydrochloride a) tert-Butyl9-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-Phenethylpyridin-2(1H)-one (817 mg, 4.10 mmol) and tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(1.5 g, 4.1 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (1.2 g, 60%) as a yellow solid:¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.1 Hz, 1H), 7.34-7.29 (m, 4H),7.26-7.20 (m, 3H), 7.03 (dd, J=8.2, 1.5 Hz, 1H), 6.50 (s, 1H), 6.09 (dd,J=6.9, 1.6 Hz, 1H), 4.63 (br s, 2H), 3.74 (br s, 2H), 3.63 (s, 3H),2.98-2.91 (m, 2H), 2.84-2.79 (m, 4H), 1.51 (s, 9H).

b)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenethylpyridin-2(1H)-onedihydrochloride

tert-Butyl9-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(1.2 g, 2.4 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (550 mg, 51%) as a yellow solid: mp 280-295° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 9.67 (s, 2H), 7.59-7.52 (m, 3H), 7.35-7.27 (m,4H), 7.24-7.17 (m, 1H), 7.01 (dd, J=7.4, 2.0 Hz, 1H), 6.38-6.27 (m, 2H),4.45 (s, 2H), 3.67 (s, 3H), 3.42 (t, J=6.4 Hz, 2H), 2.97-2.89 (m, 4H),2.81-2.76 (m, 2H); ESI MS m/z 384 [M+H]; HPLC (Method B)>99% (AUC),t_(R)=13.3 min.

Example 57 Preparation of4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(5-Chloropyridin-2-yl)pyridin-2(1H)-one (111 mg, 0.537 mmol) andtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.54 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (80 mg, 30%) as a green solid: ¹HNMR (500 MHz, CDCl₃) δ 8.69 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.5, 2.4 Hz,1H), 7.74 (d, J=8.5 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.36 (d, J=1.5 Hz,1H), 7.17 (d, J=1.5 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.98 (dd, J=7.1,1.8 Hz, 1H), 4.65 (br s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.83 (br s,2H), 1.50 (s, 9H).

b)4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(80 mg, 0.16 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (40 mg, 54%) as a white solid: ¹H NMR (500 MHz,CD₃OD) δ 8.74 (d, J=2.4 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.02 (dd,J=8.7, 2.4 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.58(d, J=1.9 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 1.8 Hz, 1H),7.15 (dd, J=8.4, 1.8 Hz, 1H), 4.50 (s, 2H), 3.75 (s, 3H), 3.68 (t, J=6.5Hz, 2H), 3.22 (t, J=6.5 Hz, 2H); ESI MS m/z 391 [M+H]⁺; HPLC (MethodB)>99% (AUC), t_(R)=12.2 min.

Example 59 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-onedihydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(75 mg, 0.19 mmol) was reacted according to the procedure of Example 47to provide the free-base. Conversion to the dihydrochloride salt usingthe procedure of Example 30 (step g) provided the title compound (71 mg,78%) as a white solid: mp 215-230° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.65(d, J=2.6 Hz, 1H), 7.91 (overlapping ddd, J=9.6, 2.1 Hz, 1H), 7.83-7.20(m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.09 (dd,J=8.4, 1.8 Hz, 1H), 6.59 (dd, J=7.5, 2.6 Hz, 1H), 6.36 (d, J=2.6 Hz,1H), 5.41 (s, 2H), 4.76 (d, J=14.2 Hz, 1H), 4.39 (d, J=14.2 Hz, 1H),3.94-3.82 (m, 2H), 3.74 (s, 3H), 3.65-3.58 (m, 2H), 3.13 (s, 3H); ESI MSm/z 419 [M+H]⁺; HPLC (Method B) 95.8% (AUC), t_(R)=110 min.

Example 60 Preparation of4-(5-Chloropyridin-2-yl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(57 mg, 0.14 mmol) was reacted according to the procedure of Example 47to provide the free-base. Conversion to the dihydrochloride salt usingthe procedure of Example 30 (step g) provided the title compound (54.5mg, 81%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.72 (d, J=1.7 Hz,1H), 8.03 (d, J=7.9 Hz, 1H), 7.99 (dd, J=8.2, 2.2 Hz, 1H), 7.79 (d,J=7.1 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.56 (d, J=1.3 Hz, 1H), 7.34 (d,J=1.5 Hz, 1H), 7.19 (dd, J=7.2, 1.8 Hz, 1H), 7.14 (dd, J=8.3, 1.8 Hz,1H), 4.80-4.72 (br m, 1H), 4.46-4.34 (m, 1H), 3.96-3.86 (m, 1H), 3.75(s, 3H), 3.65-3.55 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z405 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.0 min.

Example 61 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(180 mg, 0.46 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (95 mg,0.56 mmol), (i-Pr)₂EtN (0.25 mL, 1.4 mmol) were combined in ethanol (2mL) and heated at 60° C. for 2 h. Purification by preparative HPLC andconversion to the dihydrochloride salt using the procedure of Example 30(step g) provided the title compound as a white solid: mp 285-289° C.;¹H NMR (300 MHz, D₂O) δ 7.50 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H),7.42-7.31 (m, 6H), 6.96 (dd, J=8.3, 1.6 Hz, 1H), 6.27 (dd, J=7.7, 2.6Hz, 1H), 6.10 (d, J=2.6 Hz, 1H), 5.90 (s, 2H), 4.59 (br s, 2H),3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J=5.7 Hz, 2H), 3.18-3.05 (brm, 2H), 2.15-1.90 (m, 4H); ESI MS m/z 483 [M+H]⁺; HPLC (Method B) 98.8%(AUC), t_(R)=11.3 min.

Example 62 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one(68 mg, 0.16 mmol) was reacted according to the procedure of Example 47to provide the free-base. Conversion to the dihydrochloride salt usingthe procedure of Example 30 (step g) provided the title compound (39.6mg, 48%) as a brown solid: mp 274-280° C.; ¹H NMR (500 MHz, CD₃OD) δ9.04 (s, 1H), 8.28 (dd, J=8.7, 1.9 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.83(d, J=7.1 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.39(d, J=1.6 Hz, 1H), 7.24 (dd, J=7.1, 1.9 Hz, 1H), 7.15 (dd, J=8.3, 1.7Hz, 1H), 4.80-4.71 (br m, 1H), 4.44-4.35 (br m, 1H), 3.96-3.86 (br m,1H), 3.75 (s, 3H), 3.67-3.57 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H); ESIMS m/z 439 [M+H]⁺; HPLC (Method B) 96.4% (AUC), t_(R)=12.6 min.

Example 63 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridazin-3-yl)pyridin-2(1H)-onedihydrochloride a) 3-(2-Methoxypyridin-4-yl)-6-methylpyridazine

3-Chloro-6-methylpyridazine (343 mg, 2.67 mmol) and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (470mg, 2.0 mmol) were reacted according to Example 31 (step a) to providethe title compound (183 mg, 45%) as a cream solid: ¹H NMR (500 MHz,CDCl₃) δ 8.31 (d, J=5.3 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.59 (dd,J=5.3, 1.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.38 (s, 1H), 4.00 (s, 3H),2.79 (s, 3H).

b) 4-(6-Methylpyridazin-3-yl)pyridin-2(1H)-one

3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (183 mg, 0.909 mmol) wasreacted according to Example 31 (step c) to provide the title compound(133 mg, 75%) as a white solid: ¹H NMR (300 MHz, CD₃OD) δ 8.12 (d, J=8.8Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.59 (d, J=6.6 Hz, 1H), 7.17-7.14 (m,2H), 2.75 (s, 3H).

c) tert-Butyl5-methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (133 mg, 0.710 mmol) andtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(259 mg, 0.71 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (200 mg, 59%) as a yellow solid:¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.7 Hz, 1H), 7.60 (d, J=7.2 Hz,1H), 7.56 (d, J=8.3 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.39 (d, J=1.6 Hz,1H), 7.29 (overlapping ddd, J=7.3, 1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H),7.11 (d, J=7.6 Hz, 1H), 4.67 (br s, 2H), 3.91-3.83 (br m, 2H), 3.67 (s,3H), 2.89-2.83 (br m, 2H), 2.53 (s, 3H), 1.52 (s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridazin-3-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.42 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (57 mg, 33%) as an orange solid: mp 310-315° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.47 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H),7.89 (d, J=7.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H),7.35 (d, J=1.6 Hz, 1H), 7.25 (dd, J=7.1, 1.9 Hz, 1H), 7.15 (dd, J=8.3,1.9 Hz, 1H), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.24(t, J=6.2 Hz, 2H), 2.85 (s, 3H); ESI MS m/z 372 [M+H]⁺; HPLC (Method B)98% (AUC), t_(R)=9.3 min.

Example 64 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridazin-3-yl)pyridin-2(1H)-onedihydrochloride

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridazin-3-yl)pyridin-2(1H)-one(77 mg, 0.21 mmol) was reacted according to the procdure of Example 47to provide the free-base. Conversion to the dihydrochloride salt usingthe procedure of Example 30 (step g) provided the title compound (60 mg,74%) as a yellow solid: mp 285-288° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.9(s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.8Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.25 (d, J=1.7Hz, 1H), 7.14-7.11 (m, 2H), 4.65 (d, J=12.1 Hz, 1H), 4.31 (dd, J=14.2,7.5 Hz, 1H), 3.81-3.74 (m, 1H), 3.71 (s, 3H), 3.55-3.45 (m, 1H),3.26-3.15 (m, 2H), 2.98 (s, 3H), 2.72 (s, 3H); ESI MS m/z 386 [M+H]⁺;HPLC (Method B)>99% (AUC), t_(R)=9.4 min.

Example 65 Preparation of4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(4-Fluoro-2-methoxyphenyl)pyridine 1-oxide

4-Chloropyridine-N-oxide (305 mg, 2.35 mmol),4-fluoro-2-methoxyphenylboronic acid (1.0 g, 8.8 mmol) were reactedaccording to the procedure of Example 39 (step a) to provide the titlecompound (450 mg, 87%) as a purple solid: ¹H NMR (300 MHz, CDCl₃) δ 8.21(d, J=7.2 Hz, 2H), 7.45 (d, J=7.2 Hz, 2H), 7.31 (d, J=6.5 Hz, 1H),6.80-6.71 (m, 2H), 3.85 (s, 3H).

b) 4-(4-Fluoro-2-methoxyphenyl)pyridin-2(1H)-one

4-(4-Fluoro-2-methoxyphenyl)pyridine 1-oxide (450 mg, 2.05 mmol) wasreacted according to the procedure of Example 32 (step b) to provide thetitle compound (291 mg, 66%) as a brown solid: ¹H NMR (300 MHz, DMSO-d₆)δ 11.4 (br s, 1H), 7.39-7.31 (m, 2H), 7.03 (d, J=10.2 Hz, 1H), 6.85(overlapping dd, J=7.4 Hz, 1H), 6.35 (s, 1H), 6.27 (d, J=6.1 Hz, 1H),3.80 (s, 3H).

c) tert-Butyl7-(4-(4-fluoro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(4-Fluoro-2-methoxyphenyl)pyridin-2(1H)-one (100 mg, 0.45 mmol) andtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(166 mg, 0.454 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (106 mg, 46%) as a yellow oil: ¹HNMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.2 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H),7.39-7.32 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.80-6.70 (m, 3H), 6.46 (dd,J=7.1, 1.9 Hz, 1H), 4.66 (br s, 2H), 3.87 (s, 3H), 3.86-3.78 (m, 2H),3.64 (s, 3H), 2.83 (t, J=6.1 Hz, 2H), 1.50 (s, 9H).

d)4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-(4-(4-fluoro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(106 mg, 0.211 mmol) was deprotected according to the procedure ofExample 30 (step e) to provide the free base (74 mg, 88%). The free-base(37 mg, 0.092 mmol) was converted to the hydrochloride salt according tothe procedure of Example 30 (steps g) to provide the title compound (35mg, 89%) as a yellow solid: mp 296-300° C.; ¹H NMR (300 MHz, DMSO-d₆) δ9.56 (br s, 2H), 7.64 (d, J=7.1 Hz, 1H), 7.62-7.55 (m, 2H), 7.47 (dd,J=8.4, 6.9 Hz, 1H), 7.12-7.06 (m, 2H), 6.90 (overlapping ddd, J=8.4, 2.4Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 6.47 (dd, J=7.1, 1.8 Hz, 1H), 4.37-4.30(br m, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.56-3.45 (br m, 2H), 3.10 (t,J=5.5 Hz, 2H); ESI MS m/z 404 [M+H]⁺; HPLC (Method B)>99% (AUC),t_(R)=12.5 min.

Example 66 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-fluoro-2-methoxyphenyl)pyridin-2(1H)-onehydrochloride

4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(37 mg, 0.092 mmol) was reacted according to the procedure of Example 47to provide the free-base. Conversion to the dihydrochloride salt usingthe procedure of Example 30 (step g) provided the title compound (21 mg,52%) as a yellow solid: mp 294-298° C.; ¹H NMR (300 MHz, DMSO-d₆) δ10.83 (br s, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.54(d, J=8.3 Hz, 1H), 7.46 (dd, J=8.4, 6.9 Hz, 1H), 7.12-7.10 (m, 1H), 7.08(d, J=1.4 Hz, 1H), 6.91 (overlapping ddd, J=8.4, 2.4 Hz, 1H), 6.55 (d,J=1.6 Hz, 1H), 6.48 (dd, J=7.1, 1.6 Hz, 1H), 4.62 (d, J=12.2 Hz, 1H),4.30 (dd, J=14.2, 7.5 Hz, 1H), 3.86 (s, 3H), 3.80-3.76 (m, 1H), 3.75 (s,3H), 3.52-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.79 (d, J=4.6 Hz, 3H); ESIMS m/z 418 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.6 min.

Example 67 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl4-(7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)piperidine-1-carboxylate

4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(100 mg, 0.26 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (27 mg,0.26 mmol) were stirred in methylene chloride (1 mL) and AcOH (0.1 mL),and pico line borane complex (27 mg, 0.26 mmol) was added. Afterstirring for 16 h, the mixture was diluted with methylene chloride,washed with sodium carbonate solution and concentrated. The obtainedresidue was purified by flash column chromatography (silica gel, (1:1EtOAc/hexanes)/(10:1 methanol/ammonia), 10:0 to 9:1) to provide thetitle compound (90 mg, 61%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.45-7.36 (m, 5H), 7.32-7.30 (m, 1H), 7.32-7.27 (m, 2H), 6.99 (dd,J=8.2, 1.6 Hz, 1H), 6.05-6.01 (m, 2H), 5.05 (s, 2H), 4.20 (s, 2H), 3.85(s, 2H), 3.60 (s, 3H), 3.04-2.93 (m, 2H), 2.88-2.66 (m, 5H), 1.98-1.87(m, 2H), 1.60-1.54 (m, 2H), 1.47 (s, 9H).

b)4-(Benzyloxy)-1-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl4-(7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)piperidine-1-carboxylate(90 mg, 0.16 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (85 mg, 100%) as an orange solid: ¹H NMR (500 MHz,D₂O) δ 7.56-7.53 (m, 2H), 7.48-7.40 (m, 6H), 7.02 (dd, J=8.4, 1.4 Hz,1H), 6.33 (dd, J=7.5, 2.4 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.16 (s, 2H),4.63 (br s, 2H), 4.09-3.79 (br m, 2H), 3.69-3.53 (m, 6H), 3.26-3.23 (m,2H), 3.14 (t, J=12.8 Hz, 2H), 2.49 (d, J=1.3 Hz, 2H), 2.16-2.04 (m, 2H);ESI MS m/z 469 [M+H]⁺; HPLC (Method B) 98.1% (AUC), t_(R)=11.4 min.

Example 68 Preparation of4-(Benzyloxy)-1-(5-methyl-2-(1-methylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

4-(Benzyloxy)-1-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(11H)-one(50 mg, 0.11 mmol) was methylated according to the procedure of Example47 to provide the title compound (30 mg, 51%) as a white solid: ¹H NMR(500 MHz, D₂O) δ 7.56-7.52 (m, 2H), 7.48-7.38 (m, 6H), 7.02 (dd, J=8.3,1.6 Hz, 1H), 6.33 (dd, J=7.5, 2.6 Hz, 1H), 6.16 (d, J=2.5 Hz, 1H), 5.16(s, 2H), 4.63 (s, 2H), 3.85-3.83 (m, 2H), 3.74-3.71 (m, 2H), 3.62 (s,3H), 3.26-3.14 (m, 5H), 2.89 (s, 3H), 2.55-2.50 (m, 2H), 2.19-2.12 (m,2H); ESI MS m/z 483 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=11.4 min.

Example 69 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onedihydrochloride a) 2′-Methoxy-6-(trifluoromethyl)-3,4′-bipyridine

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.24g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g, 11 mmol)were reacted according to the procedure of Example 31 (step a) toprovide the title compound (1.1 g, 81%) as a white solid: ESI MS m/z 255[M+H].

b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one

2′-Methoxy-6-(trifluoromethyl)-3,4′-bipyridine (1.1 g, 4.3 mmol) wasreacted according to the procedure of Example 31 (step c) to provide thetitle compound (522 mg, 50%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 11.8 (br s, 1H), 9.10 (s, 1H), 8.40 (dd, J=8.1, 1.2 Hz, 1H), 8.00 (d,J=8.2 Hz, 1H), 7.56 (d, J=6.7 Hz, 1H), 6.81 (s, 1H), 6.63 (dd, J=6.7,1.3 Hz, 1H).

c) tert-Butyl5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (131 mg, 0.54 mmol)and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.54 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (167 mg, 59%) as a green solid:¹H NMR (300 MHz, CDCl₃) δ 8.99 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.1, 1.8Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.60-7.54 (m, 2H), 7.32 (d, J=1.9 Hz,1H), 7.07 (d, J=8.0 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.49 (dd, J=7.1,2.0 Hz, 1H), 4.66 (s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (s, 2H),1.50 (s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(165 mg, 0.315 mmol) was deprotected and converted to thedihydrochloride salt according to the procedure of Example 30 (steps eand g) to provide the title compound (40 mg, 26%) as a yellow solid ¹HNMR (300 MHz, CD₃OD) δ 9.10 (d, J=2.0 Hz, 1H), 8.41 (dd, J=8.2, 1.7 Hz,1H), 7.98 (d, J=8.2 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.61 (d, J=8.2 Hz,1H), 7.57 (d, J=1.6 Hz, 1H), 7.14 (dd, J=8.3, 1.9 Hz, 1H), 7.02 (d,J=1.6 Hz, 1H), 6.89 (dd, J=7.1, 2.0 Hz, 1H), 4.49 (s, 2H), 3.76 (s, 3H),3.68 (t, J=6.2 Hz, 2H), 3.22 (t, J=6.2 Hz, 2H); ESI MS m/z 425 [M+H]⁺;HPLC (Method B)>99% (AUC), t_(R)=12.3 min.

Example 70 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one(77 mg, 0.18 mmol) was reacted according to the procedure of Example 47and converted to the dihydrochloride to provide the title compound (27mg, 29%) as a yellow solid: mp 295-300° C.; ¹H NMR (500 MHz, CD₃OD) δ9.09 (d, J=1.7 Hz, 1H), 8.42 (dd, J=8.1, 2.0 Hz, 1H), 7.97 (d, J=8.2 Hz,1H), 7.85 (d, J=7.1 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.5 Hz,1H), 7.15 (dd, J=8.3, 1.8 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 6.89 (dd,J=7.1, 2.0 Hz, 1H), 4.79-4.37 (br m, 2H), 3.90-3.60 (br m, 5H), 3.30 (brm, 2H), 3.14 (s, 3H); ESI MS m/z 439 [M+H]⁺; HPLC (Method B)>99% (AUC),t_(R)=12.4 min.

Example 71 Preparation of1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(1.07 g, 3.04 mmol) was reacted according to the procedure of Example 87(step a) to provide the title compound (1.39 g, 91%) as a white solid:¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.66 (d, J=6.6 Hz, 2H), 7.35 (d,J=8.2 Hz, 1H), 7.28-7.21 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 4.47 (s, 2H),3.77-3.65 (br m, 2H), 3.11-3.03 (br m, 2H), 2.36 (s, 3H), 1.48 (s, 9H).

b) tert-Butyl7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (131 mg, 0.545mmol) and tert-butyl7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(255 mg, 0.505 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (125 mg, 34%) as a yellow oil: ¹HNMR (300 MHz, CDCl₃) δ 9.01 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 8.08 (dd,J=8.3, 1.9 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.57(d, J=7.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.33 (dd, J=8.2, 1.6 Hz, 1H),7.29-7.23 (m, 4H), 7.09 (dd, J=7.2, 1.8 Hz, 1H), 4.52 (s, 2H), 3.80-3.73(br m, 2H), 3.18-3.09 (br m, 2H), 2.35 (s, 3H), 1.50 (s, 9H).

b)1-(5-Tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onetrifluoroacetic acid salt

tert-Butyl7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(165 mg, 0.248 mmol) was stirred in TFA (3 mL) and methylene chloride (1mL) for 3 h. Concentration of the solution under reduced pressureprovided the title compound (164 mg, 100%) as a yellow oil; ESI MS m/z565 [M+H]⁺.

c)1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

1-(5-Tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onetrifluoroacetic acid salt (163 mg, 0.248 mmol) was deprotected andconverted to the dihydrochloride salt according to the procedure ofExample 106 (step b) to provide the title compound (30 mg, 25%) as anorange solid: mp 308-313° C.; ¹H NMR (500 MHz, CD₃OD) δ 9.04 (s, 1H),8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 7.81 (d, J=7.0 Hz,1H), 7.62 (d, J=8.3 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.38 (d, J=1.8 Hz,1H), 7.24 (dd, J=7.1, 2.0 Hz, 1H), 7.11 (dd, J=8.3, 2.0 Hz, 1H), 4.49(s, 2H), 3.65 (t, J=6.2 Hz, 2H), 3.21 (t, J=6.2 Hz, 2H); ESI MS m/z 411[M+H]⁺; HPLC (Method B) 97.6% (AUC), t_(R)=12.4 min.

Example 72 Preparation of1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-bromo-5-(triisopropylsilyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(300 mg, 0.85 mmol) was dissolved in DMF (3 mL), and NaH (60% weightdispersion in mineral oil, 40 mg, 1.02 mmol) and TIPSCl (164 mg, 1.02mmol) were added. After stirring for 1 h, the mixture was poured intowater and extracted with EtOAc. Concentration of the organic extractsand purification of the residue by flash column chromatography (silicagel, EtOAc/hexanes) provided the title compound (262 mg, 61%) as a clearoil: ¹H NMR (300 MHz, CDCl₃) δ 7.70 (s, 1H), 7.25 (d, J=8.2 Hz, 1H),7.19 (dd, J=8.2, 1.4 Hz, 1H), 4.59 (s, 2H), 3.76-3.71 (br m, 2H),2.96-2.90 (br m, 2H), 1.81-1.71 (m, 3H), 1.51 (s, 9H), 1.15 (d, J=7.5Hz, 18H).

b) tert-Butyl7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

tert-Butyl7-bromo-5-(triisopropylsilyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(260 mg, 0.51 mmol) and4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (123 mg, 0.510mmol) were reacted according to the procedure of Example 30 (step g) toprovide the title compound (80 mg, 30%) as a yellow solid: ESI MS m/z512 [M+H]⁺.

c)1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(80 mg, 0.15 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (30 mg, 44%) as an orange solid: mp 314-318° C.; ¹HNMR (300 MHz, CD₃OD) δ 8.52 (d, J=8.9 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H),7.89 (d, J=7.2 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H),7.43 (d, J=1.5 Hz, 1H), 7.33 (dd, J=7.2, 2.0 Hz, 1H), 7.14 (dd, J=7.4,2.0 Hz, 1H), 4.49 (s, 2H), 3.65 (t, J=6.2 Hz, 2H), 3.21 (t, J=6.2 Hz,2H); ESI MS m/z 412 [M+H]⁺; HPLC (Method B) 96.0% (AUC), t_(R)=11.6 min.

Example 73 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-onehydrochloride a) 5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 13 mmol)were reacted according to the procedure of Example 31 (step a) toprovide the title compound (1.0 g, 46%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 9.10 (s, 2H), 8.35 (d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 4.02 (s, 3H).

b) 4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one

5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (900 mg, 3.5mmol) was reacted according to the procedure of Example 31 (step c) toprovide the title compound (470 mg, 56%) as an orange solid: ¹H NMR (300MHz, DMSO-d₆) δ 11.6 (br s, 1H), 9.41 (s, 2H), 7.61 (d, J=6.8 Hz, 1H),6.91 (s, 1H), 6.68 (dd, J=6.8, 1.6 Hz, 1H).

c) tert-Butyl5-methyl-7-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (100 mg, 0.42mmol) and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(116 mg, 0.32 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (41 mg, 24%) as a yellow oil: ESIMS m/z 526 [M+H]⁺.

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(41 mg, 0.078 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (29 mg, 80%) as a yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 9.51 (s, 2H), 9.37 (br s, 2H), 7.90 (d, J=7.2 Hz, 1H),7.62-7.60 (m, 2H), 7.13 (d, J=1.9 Hz, 1H), 7.10 (dd, J=8.3, 1.7 Hz, 1H),6.88 (dd, J=7.1, 2.0 Hz, 1H), 4.38-4.34 (br m, 2H), 3.70 (s, 3H),3.56-3.50 (br m, 2H), 3.11 (t, J=5.8 Hz, 2H); ESI MS m/z 426 [M+H]⁺;HPLC (Method B)>100% (AUC), t_(R)=12.2 min.

Example 74 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-onehydrochloride a) 2-(2-Methoxypyridin-4-yl)-5-(trifluoromethyl)pyrimidine

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.66g, 7.06 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (1.3 g, 7.1mmol) were reacted according to the procedure of Example 31 (step a) toprovide the title compound (307 mg, 16%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 9.08 (s, 2H), 8.34 (d, J=5.3 Hz, 1H), 7.89 (dd, J=5.3, 1.4Hz, 1H), 7.81 (s, 1H), 4.01 (s, 3H).

b) 4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-one

2-(2-Methoxypyridin-4-yl)-5-(trifluoromethyl)pyrimidine (400 mg, 1.56mmol) was reacted according to the procedure of Example 31 (step c) toprovide the title compound (200 mg, 63%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 11.9 (br s, 1H), 9.43 (s, 2H), 7.58 (d, J=6.8 Hz, 1H),7.34 (s, 1H), 7.06 (dd, J=6.8, 1.7 Hz, 1H).

c) tert-Butyl5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-one (100 mg, 0.34mmol) and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(124 mg, 0.339 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (70 mg, 39%) as a yellow solid:¹H NMR (300 MHz, CDCl₃) δ 9.11 (s, 2H), 7.86 (s, 1H), 7.59-7.53 (m, 2H),7.38 (s, 1H), 7.28-7.26 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.89-4.63 (brm, 2H), 3.90-3.80 (br m, 2H), 3.65 (s, 3H), 2.88-2.79 (br m, 2H), 1.50(s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(70 mg, 0.13 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (51 mg, 87%) as a yellow solid: mp 301-309° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 9.48 (s, 2H), 9.37 (br s, 2H), 7.89 (d, J=7.2Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.50 (d, J=1.6Hz, 1H), 7.21 (dd, J=7.6, 1.9 Hz, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H),4.41-4.31 (br m, 2H), 3.71 (s, 3H), 3.51-3.48 (br m, 2H), 3.10 (t, J=5.6Hz, 2H); ESI MS m/z 426 [M+H]⁺; HPLC (Method B) 97.9% (AUC), t_(R)=12.6min.

Example 75 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride a)2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine

4-BromoBromo-2-methoxypyridine (3.06 g, 16.2 mmol),(6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol),3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74mmol) and Cs₂CO₃ (7.57 g, 23.2 mmol) were combined in toluene (15 mL)and heated to reflux under a nitrogen atmosphere for 16 h. Upon coolingthe mixture was purified by flash column chromagraphy (silica gel,hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%)as a red oil: ¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz,1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9,2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).

b) 4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one

2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (3.19 g,11.2 mmol) was reacted according to the procedure of Example 31 (step c)to provide the title compound (2.04 g, 67%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 11.2 (br s, 1H), 8.84 (s, 1H), 8.14 (d, J=8.5 Hz,1H), 7.96 (d, J=8.0 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.3,2.5 Hz, 1H), 5.82 (d, J=2.4 Hz, 1H), 5.25 (s, 2H).

c) tert-Butyl5-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (177 mg,0.655 mmol) and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(200 mg, 0.54 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (120 mg, 40%) as a yellow oil: ¹HNMR (300 MHz, CDCl₃) δ 8.80 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.76 (d,J=8.0 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (m,1H), 7.01 (d, J=8.1 Hz, 1H), 6.06-6.04 (m, 2H), 5.16 (s, 2H), 4.65-4.60(br m, 2H), 3.89-3.79 (br m, 2H), 3.63 (s, 3H), 2.87-2.78 (br m, 2H),1.50 (s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(120 mg, 0.21 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (90 mg, 81%) as a white solid: mp 286-291° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.54 (br s, 2H), 8.89 (s, 1H), 8.19 (dd, J=7.9, 1.4Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.3Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 6.98 (dd, J=8.3, 1.8 Hz, 1H), 6.15 (dd,J=7.5, 2.7 Hz, 1H), 6.02 (d, J=2.7 Hz, 1H), 5.35 (s, 2H), 4.35-4.30 (brm, 2H), 3.67 (s, 3H), 3.53-3.47 (br m, 2H), 3.09 (t, J=5.8 Hz, 2H); ESIMS m/z 455 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.7 min.

Example 76 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-2(1H)-onea) tert-Butyl5-methyl-7-(2-oxo-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

2-(Bromomethyl)-5-(trifluoromethyl)pyridine (140 mg, 0.58 mmol),tert-butyl7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(230 mg, 0.58 mmol) and K₂CO₃ (160 mg, 1.16 mmol) were stirred inacetonitrile/DMF (3 mL/0.5 mL) for 72 h. The mixture was diluted withmethylene chloride, washed with water and concentrated to provide thetitle compound (96 mg, 29%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ8.88 (s, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.51(d, J=8.2 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.00 (d,J=7.7 Hz, 1H), 6.12 (dd, J=7.6, 2.7 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H),5.26 (s, 2H), 4.63-4.58 (br m, 2H), 3.87-3.76 (br m, 2H), 3.63 (s, 3H),2.86-2.76 (br m, 2H), 1.50 (s, 9H).

b)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(2-oxo-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(90 mg, 0.16 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (76 mg, 90%) as a white solid: mp 296-300° C.; ¹H NMR(300 MHz, CD₃OD) δ 8.93 (s, 1H), 8.23 (dd, J=8.2, 2.1 Hz, 1H), 7.82 (d,J=8.2 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.49 (d,J=1.7 Hz, 1H), 7.06 (dd, J=8.3, 1.8 Hz, 1H), 6.47 (dd, J=7.5, 2.7 Hz,1H), 6.20 (d, J=2.6 Hz, 1H), 5.42 (s, 2H), 4.48 (s, 2H), 3.73 (s, 3H),3.67 (t, J=6.1 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESI MS m/z 455 [M+H]⁺;HPLC (Method B) 97.6% (AUC), t_(R)=12.6 min.

Example 77 Preparation of5-(Benzyloxy)-2-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridazin-3(2H)-onehydrochloride a) 5-(Benzyloxy)pyridazin-3(2H)-one

CAS Registry Number 1008517-73-4

This compound was prepared in accordance with the procedure of Stenkampet al., WO 2008/022979.

b) tert-Butyl7-(4-(benzyloxy)-6-oxopyridazin-1(6H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

5-(Benzyloxy)pyridazin-3(2H)-one (100 mg, 0.5 mmol) and tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(180 mg, 0.5 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (106 mg, 43%) as a solid: ESI MSm/z 487 [M+H]⁺.

c)5-(Benzyloxy)-2-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridazin-3(2H)-onehydrochloride

tert-Butyl7-(4-(benzyloxy)-6-oxopyridazin-1(6H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(100 mg, 0.2 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (30 mg, 35%) as a white solid: mp 261-265° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.23 (s, 2H), 7.96 (d, J=2.8 Hz, 1H), 7.59 (d,J=1.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.51-7.48 (m, 2H), 7.46-7.42 (m,2H), 7.40 (d, J=7.5 Hz, 1H), 7.13 (dd, J=8.4, 1.7 Hz, 1H), 6.51 (d,J=2.8 Hz, 1H), 5.22 (s, 2H), 4.34 (s, 2H), 3.69 (s, 3H), 3.52 (t, J=5.8Hz, 2H), 3.09 (t, J=5.8 Hz, 2H); ESI MS m/z 387 [M+H]⁺; HPLC (Method B)97.7% (AUC), t_(R)=12.8 min.

Example 78 Preparation of2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-onehydrochloride a)5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

CAS Registry Number 1008517-74-5

This compound was prepared in accordance with the procedure of Stenkampet al., WO 2008/022979.

b) 6-Oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yltrifluoromethanesulfonate

5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.4 g, 13mmol) dissolved in methylene chloride (75 mL) and cooled to 0° C.Triethylamine (3.5 mL, 25 mmol) and Tf₂O (2.3 mL, 14 mmol) were addedand the mixture stirred for a further 2.5 h. Saturated NaHCO₃ solutionwas added and the organic phase removed, dried over Na₂SO₄ andconcentrated. Purification by flash column chromaotgraphy (silica gel,EtOAc/hexanes) provided the title compound (2.47 g, 60%) as a yellowoil: ¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J=2.8 Hz, 1H), 6.86 (d, J=2.7Hz, 1H), 6.01 (dd, J=10.2, 2.2 Hz, 1H), 4.15-4.12 (m, 1H), 3.75 (dt,J=11.6, 2.5 Hz, 1H), 2.18-2.02 (m, 2H), 1.78-1.66 (m, 3H), 1.62-1.55 (m,1H).

c)2-(Tetrahydro-2H-pyran-2-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-one

6-Oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yltrifluoromethanesulfonate (2.47 g, 7.5 mmol) and4-trifluoromethylphenylboronic acid (2.56 g, 15 mmol) were reactedaccording to the procedure of Example 31 (step a) to provide the titlecompound (500 mg, 20%) as a white solid: ESI MS m/z 325 [M+H]⁺.

d) 5-(4-(Trifluoromethyl)phenyl)pyridazin-3(2H)-one

2-(Tetrahydro-2H-pyran-2-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-one(500 mg, 1.54 mmol) was reacted according to the procedure of Example 31(step c) to provide the title compound (100 mg, 27%) as a solid: ESI MSm/z 241 [M+H].

e) tert-Butyl5-methyl-7-(6-oxo-4-(4-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

5-(4-(Trifluoromethyl)phenyl)pyridazin-3(2H)-one (100 mg, 0.41 mmol) andtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(151 mg, 0.41 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (65 mg, 30%) as a yellow solid:¹H NMR (300 MHz, CDCl₃) δ 8.20 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.76 (d,J=8.4 Hz, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.31 (d,J=6.9 Hz, 1H), 7.26-7.24 (m, 1H), 4.62 (s, 2H), 3.89-3.80 (br m, 2H),3.66 (s, 3H), 2.84 (br m, 2H), 1.51 (s, 9H).

f)2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-onehydrochloride

tert-Butyl5-methyl-7-(6-oxo-4-(4-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(65 mg, 0.12 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (47 mg, 80%) as an orange solid: mp 315-320° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 9.37 (s, 2H), 8.56 (d, J=2.2 Hz, 1H), 8.13 (d,J=Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.72 (d, J=1.6 Hz, 1H), 7.61 (d,J=8.4 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 7.25 (dd, J=8.4, 1.8 Hz, 1H),4.36 (s, 2H), 3.70 (s, 3H), 3.58-3.48 (br m, 2H), 3.11 (t, J=5.7 Hz,2H); ESI MS m/z 425 [M+H]⁺; HPLC (Method A) 96.6% (AUC), t_(R)=15.7 min.Example 79 Preparation of4-(5-Chloropyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

tert-Butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(200 mg, 0.549 mmol) and 4-(5-chloropyridin-2-yl)pyridin-2(1H)-one (87mg, 0.42 mmol) were reacted following the procedure of Example 30 (stepg) to provide the title compound (97 mg, 47%) as a yellow solid: ¹H NMR(300 MHz, CDCl₃) δ 8.69 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.5, 2.3 Hz, 1H),7.75 (d, J=8.4 Hz, 1H), 7.55 (overlapping dd, J=7.4 Hz, 2H), 7.36 (s,1H), 7.18 (d, J=1.7 Hz, 1H), 7.08 (dd, J=8.3, 1.6 Hz, 1H), 7.00 (dd,J=7.1, 1.8 Hz, 1H), 4.65 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82(br m, 2H), 1.52 (s, 9H).

b)4-(5-Chloropyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(5H)-carboxylate(97 mg, 0.20 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound as a orange solid (68 mg, 88%): mp 310-320° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.73 (dd, J=2.4, 0.6 Hz, 1H), 8.03 (dd, J=8.5,0.5 Hz, 1H), 8.00 (dd, J=8.5, 2.4 Hz, 1H), 7.80 (d, J=7.1 Hz, 1H), 7.67(d, J=8.3 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.31 (d, J=1.7 Hz, 1H), 7.19(dd, J=7.1, 2.0 Hz, 1H), 7.14 (dd, J=8.4, 1.8 Hz, 1H), 4.56 (s, 2H),3.74 (s, 3H), 3.61 (t, J=6.1 Hz, 2H), 3.14 (t, J=6.1 Hz, 2H); ESI MS m/z391 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=11.9 min.

Example 80 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-chloropyridin-2-yl)pyridin-2(1H)-onehydrochloride

4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(104 mg, 0.266 mmol) was reacted following the procedure of Example 47to provide the title compound (75 mg, 70%) as a yellow solid: mp283-295° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.73 (d, J=2.3 Hz, 1H), 8.03 (d,J=8.5 Hz, 1H) 7.99 (dd, J=8.5, 2.3 Hz, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.67(d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.19 (dd,J=7.1, 1.8 Hz, 1H), 7.15 (dd, J=8.3, 1.7 Hz, 1H), 4.65 (br s, 2H), 3.74(m, 5H), 3.21 (t, J=5.7 Hz, 2H), 3.17 (s, 3H); ESI MS m/z 405 [M+H]⁺;HPLC (Method B) 98.7% (AUC), t_(R)=12.1 min.

Example 81 Preparation of4-(5-(Trifluoromethyl)pyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl9-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

tert-Butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(100 mg, 0.417 mmol) and4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (197 mg, 0.542mmol), were reacted following the procedure of Example 30 (step g) toprovide the title compound (168 mg, 66%) as a yellow solid: ¹H NMR (300MHz, CDCl₃) δ 9.00 (s, 1H), 8.07 (dd, J=8.3, 1.9 Hz, 1H), 7.90 (d, J=8.3Hz, 1H), 7.58 (overlapping dd, J=7.1 Hz, 2H), 7.37 (s, 1H), 7.26 (d, 1Hunder solvent), 7.08 (dd, J=8.3, 1.7 Hz, 1H), 7.03 (dd, J=7.1, 1.9 Hz,1H), 4.66 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52(s, 9H).

b)4-(5-(Trifluoromethyl)pyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl9-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(168 mg, 0.321 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound as an orange solid (73 mg, 54%): mp 305-315° C.; ¹HNMR (500 MHz, CD₃OD) δ 9.05 (s, 1H), 8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.22(d, J=8.3, Hz, 1H), 7.84 (d, J=7.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.58(d, J=1.8 Hz, 1H), 7.40 (d, J=1.8 Hz, 1H), 7.25 (dd, J=7.2, 2.0 Hz, 1H),7.15 (dd, J=8.4, 1.8 Hz, 1H), 4.57 (s, 2H), 3.74 (s, 3H), 3.62 (t, J=6.1Hz, 2H), 3.15 (t, J=5.9 Hz, 2H); ESI MS m/z 425 [M+H]⁺; HPLC (Method A)96.4% (AUC), t_(R)=12.6 min.

Example 82 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

4-(5-(Trifluoromethyl)pyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(125 mg, 0.294 mmol) was reacted following the procedure of Example 47to provide the title compound (97.9 g, 78%) as a yellow solid: mp280-290° C.; ¹H NMR (500 MHz, CD₃OD) δ 9.05 (s, 1H), 8.28 (dd, J=8.3,2.1 Hz, 1H) 8.22 (d, J=8.4, Hz, 1H), 7.84 (d, J=7.1 Hz, 1H), 7.68 (d,J=8.3 Hz, 1H), 7.59 (d, J=1.6, 1H), 7.40 (d, J=1.7 Hz, 1H), 7.25 (dd,J=7.2, 1.9 Hz, 1H), 7.16 (dd, J=8.3, 1.8 Hz, 1H), 4.87 (s, 1H), 4.51 (s,1H), 3.87 (s, 1H), 3.75 (br s, 3H), 3.55 (br s, 1H), 3.21-3.17 (m, 5H);ESI MS m/z 439 [M+H]⁺; HPLC (Method B) 98.3% (AUC), t_(R)=12.8 min.

Example 84 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

tert-Butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(306 mg, 0.840 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (142 mg,0.640 mmol) were reacted following the procedure of Example 30 (step g)to provide the title compound (157 mg, 49%) as a yellow/green solid: ¹HNMR (300 MHz, CDCl₃) δ 8.49 (d, J=2.0 Hz, 1H), 7.54-7.46 (m, 3H),7.34-7.28 (m, 2H), 7.01 (dd, J=8.2, 1.8 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H),6.07 (s, 1H), 5.17 (s, 2H), 4.63 (br m, 2H), 3.74 (br m, 2H), 3.62 (s,3H), 2.80 (br m, 2H), 1.51 (s, 9H).

b)4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(157 mg, 0.312 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound as a yellow solid (72.7 mg, 54%): mp 285-295° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.51 (s, 1H), 7.72-7.59 (m, 4H), 7.46 (d, J=1.0Hz, 1H), 7.05 (dd, J=8.3, 1.5 Hz, 1H), 6.32 (dd, J=7.6, 2.6 Hz, 1H),7.05 (d, J=2.6 Hz, 1H), 5.26 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60(t, J=6.0 Hz, 2H), 3.12 (t, J=5.8 Hz, 2H); ESI MS m/z 405 [M+H]⁺; HPLC(Method B) 98.3% (AUC), t_(R)=12.0 min.

Example 85 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-onehydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(76 mg, 0.19 mmol) was reacted following the procedure of Example 47 toprovide the title compound (61 mg, 79%) as a yellow solid: mp 287-300°C.; ¹H NMR (500 MHz, CD₃OD) δ 8.51 (d, J=2.6 Hz, 1H), 7.72-7.59 (m, 4H),7.47 (s, 1H), 7.06 (dd, J=8.3, 1.7 Hz, 1H), 6.32 (dd, J=7.6, 2.6 Hz,1H), 6.13 (d, J=2.6 Hz, 1H), 5.26 (s, 2H), 4.68 (m, 2H), 3.71 (m, 5H),3.18 (t, J=5.9 Hz, 2H), 3.15 (s, 3H); ESI MS m/z 419 [M+H]⁺; HPLC(Method B) 98.4% (AUC), t_(R)=11.1 min.

Example 86 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl9-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (145 mg, 0.604mmol) and tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(200 mg, 0.549 mmol) were coupled following the procedure of Example 30(step g) to provide the title compound (129 mg, 45%) as a yellow/greensolid: ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.10 (dd, J=8.1, 2.0 Hz,1H), 7.82 (d, J=8.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.36 (s, 1H), 7.08 (dd,J=8.3, 1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.49 (dd, J=7.1, 2.0 Hz,1H), 4.66 (br m, 2H), 3.76 (br m, 2H), 3.66 (s, 3H), 2.82 (br m, 2H),1.52 (s, 9H).

b)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl9-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(129 mg, 0.25 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (67 mg, 58%) as a yellow/brown solid: mp 315-320° C.;¹H NMR (500 MHz, CD₃OD) δ 9.10 (d, J=1.9 Hz, 1H), 8.41 (dd, J=8.2, 2.2Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.85 (d, J=7.0 Hz, 1H), 7.68 (d, J=8.3Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.15 (dd, J=8.3, 1.8 Hz, 1H), 7.03 (d,J=1.8 Hz, 1H), 6.89 (dd, J=7.1, 2.0 Hz, 1H), 4.57 (br m, 2H), 3.75 (s,3H), 3.62 (br m, 2H), 3.15 (br m, 2H); ESI MS m/z 425 [M+H]⁺; HPLC(Method B) 97.4% (AUC), t_(R)=12.3 min.

Example 87 Preparation of1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

6 N NaOH solution (6 mL), (Bu₄N)₂SO₄ (50% wt. solution in H₂O, 0.20 mL),and TsCl (646 mg, 3.39 mmol) were added to a suspension of tert-butyl7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (991 mg,2.82 mmol) in toluene (20 mL) and the resulting suspension was stirredat 25° C. for 1.5 h. H₂O and EtOAc were added to the suspension and thephases were separated. The organic phase was washed with H₂O, dried overNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound (1.285 g, 90%) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ 8.32(d, J=1.5 Hz, 1H), 7.78-7.66 (m, 2H), 7.36 (dd, J=8.4, 1.5 Hz, 1H),7.25-7.21 (m, 2H), 7.21-7.13 (m, 1H), 4.92-4.81 (m, 2H), 3.74-3.63 (m,2H), 2.70-2.61 (m, 2H), 2.37 (s, 3H), 1.50 (s, 9H).

b) tert-Butyl7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (200 mg, 0.830mmol) and tert-butyl7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(419 mg, 0.830 mmol) were coupled following the procedure of Example 30(step g) to provide the title compound (222 mg, 40%) as a yellow solid:¹H NMR (500 MHz, CDCl₃) δ 9.02 (s, 1H), 8.26 (s, 1H), 8.08 (d, J=7.6 Hz,1H), 7.80 (br s, 2H), 7.57 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H),7.47 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.27 (3H, under solventpeak), 7.07 (d, J=6.8 Hz, 1H), 4.91 (br m, 2H), 3.71 (br m, 2H), 2.71(br m, 2H), 2.36 (s, 3H), 1.52 (s, 9H).

c)1-(9-Tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

tert-Butyl7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(222 mg, 0.334 mmol) was deprotected according to the procedure ofExample 30 (step e) to provide the title compound (131 mg, 58%) as ayellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 8.25 (d, J=1.6 Hz,1H), 8.08 (dd, J=8.3, 1.9 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.75 (d,J=8.4 Hz, 2H), 7.58 (d, J=7.2 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.32 (dd,J=8.3, 1.8 Hz, 1H), 7.28-7.24 (3H, under solvent peak), 7.08 (dd, J=7.2,2.0 Hz, 1H), 4.30 (br s, 2H), 3.13 (t, J=5.6 Hz, 2H), 3.61 (br m, 2H),2.36 (s, 3H).

d)1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

1-(9-Tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one(130 mg, 0.23 mmol) was deprotected according to the procedure ofExample 106 (step b) to provide the title compound (39.5 mg, 36%) as ayellow solid: mp 320-330° C.; ¹H NMR (500 MHz, CD₃OD) δ 9.05 (s, 1H),8.28 (dd, J=8.4, 2.1 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.82 (d, J=7.2 Hz,1H), 7.66 (d, J=8.4 Hz, 1H), 7.48 (d, J=7.1 Hz, 1H), 7.39 (d, J=1.7 Hz,1H), 7.24 (dd, J=7.2, 1.9 Hz, 1H), 7.13 (dd, J=8.4, 1.8 Hz, 1H), 4.50(s, 2H), 3.63 (t, J=6.1 Hz, 2H), 3.14 (t, J=6.1 Hz, 2H); ESI MS m/z 411[M+H]⁺; HPLC (Method B) 98.4% (AUC), t_(R)=12.6 min.

Example 88 Preparation of5-(Benzyloxy)-2-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridazin-3(2H)-onehydrochloride a) tert-Butyl7-(4-(benzyloxy)-6-oxopyridazin-1(6H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

5-(Benzyloxy)pyridazin-3(2H)-one (197 mg, 0.974 mmol) and tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(353 mg, 0.966 mmol) were coupled following the procedure of Example 30(step g) to provide the title compound (130 mg, 28%) as a yellow/greensolid: ¹H NMR (300 MHz, CDCl₃) δ 7.77 (d, J=2.7 Hz, 1H), 7.52 (d, J=8.2Hz, 1H), 7.45-7.40 (m, 7H), 7.21 (dd, J=8.4, 1.5 Hz, 1H), 5.08 (s, 2H),4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52(s, 9H).

b)5-(Benzyloxy)-2-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridazin-3(2H)-onehydrochloride

tert-Butyl7-(4-(benzyloxy)-6-oxopyridazin-1(6H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(130 mg, 0.27 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (55.7, 48%) as a yellow solid: mp 235-245° C.; ¹H NMR(500 MHz, CD₃OD) δ 7.93 (d, J=2.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.56(d, J=1.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.43 (overlapping dd, J=7.8 Hz,2H), 7.39 (d, J=1.7 Hz, 1H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 6.48 (d,J=2.7 Hz, 1H), 5.22 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.59 (t, J=5.6Hz, 2H), 3.12 (t, J=5.9 Hz, 2H); ESI MS m/z 387 [M+H]⁺; HPLC (MethodB)>99% (AUC), t_(R)=11.7 min.

Example 89 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride a) tert-Butyl9-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (100 mg,0.37 mmol) and tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(135 mg, 0.370 mmol) were coupled following the procedure of Example 30(step g) to provide the title compound (44 mg, 21%) as a yellow/brownsolid: ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 7.96 (d, J=8.6 Hz, 1H),7.75 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.37-7.34 (m, 1H), 7.27(1H, under solvent peak), 7.02 (dd, J=8.3, 1.7 Hz, 1H), 6.07-6.04 (m,2H), 5.16 (s, 2H), 4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80(br m, 2H), 1.52 (s, 9H).

b)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride

tert-Butyl9-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(44 mg, 0.079 mmol) was deprotected and converted to the hydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (28 mg, 65%) as a yellow solid: mp 285-295° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.75 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.79 (d,J=8.1 Hz, 1H), 7.53 (dd, J=7.9, 2.0 Hz, 2H), 7.38 (d, J=1.7 Hz, 1H),6.97 (dd, J=8.4, 1.8 Hz, 1H), 6.25 (dd, J=7.6, 2.7 Hz, 1H), 6.08 (d,J=2.6 Hz, 1H), 5.26 (s, 2H), 4.46 (s, 2H), 3.63 (s, 3H), 3.51 (t, J=6.1Hz, 2H), 3.03 (t, J=6.1 Hz, 2H); ESI MS m/z 455 [M+H]⁺; HPLC (MethodB)>99% (AUC), t_(R)=12.8 min.

Example 90 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-methylpyridin-2-yl)pyridin-2(1H)-onedihydrochloride a) 2′-Methoxy-5-methyl-2,4′-bipyridine

2-Bromo-5-methylpyridine (2.93 g, 17.0 mmol) and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.34g, 14.2 mmol) were reacted according to Example 31 (step a) to providethe title compound (1.2 g, 42%) as a brown solid: ESI MS m/z 201 [M+H]⁺.

b) 4-(5-Methylpyridin-2-yl)pyridin-2(1H)-one

2′-Methoxy-5-methyl-2,4′-bipyridine (1.2 g, 6.0 mmol) was reactedaccording to Example 31 (step c) to provide the title compound (301 mg,27%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.58 (s, 1H) 8.53(s, 1H), 7.88 (overlapping dd, J=8.2 Hz, 1H), 7.71 (d, J=6.0 Hz, 1H),7.43 (d, J=7.7, 1H), 6.95 (d, J=1.5 Hz, 1H), 6.84 (dd, J=6.9, 1.7 Hz,1H), 2.34 (s, 3H).

c) tert-Butyl9-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(5-methylpyridin-2-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) andtert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(294 mg, 0.805 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (138 mg, 36%) as a yellow/greensolid: ¹H NMR (500 MHz, CDCl₃) δ 8.56 (s, 1H), 7.71 (d, J=8.2 Hz, 1H),7.63-7.61 (m, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.37(s, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.09 (dd, J=8.3, 1.7 Hz, 1H), 7.04 (dd,J=7.2, 1.9 Hz, 1H), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82(br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).

d)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-methylpyridin-2-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl9-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(138 mg, 0.27 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (18 mg, 15%) as a yellow solid: mp 303-310° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.59 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.87 (d,J=6.5 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.56 (d,J=1.4 Hz, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.15-7.12 (m, 2H), 4.57 (s, 2H),3.74 (s, 3H), 3.61 (t, J=6.0 Hz, 2H), 3.14 (t, J=6.1 Hz, 2H), 2.46 (s,3H); ESI MS m/z 371 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=11.0 min.

Example 91 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-methylpyridin-2-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl5-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(5-Methylpyridin-2-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) andtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(294 mg, 0.805 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (245 mg, 64%) as a yellow/greensolid: ¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.64-7.60 (m, 1H), 7.55-7.51 (m, 2H), 7.37 (d, J=1.6 Hz, 1H),7.17 (d, J=1.6 Hz, 1H), 7.10-7.03 (m, 2H), 4.66 (br m, 2H), 3.85 (br m,2H), 3.65 (s, 3H), 2.84 (br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).

b)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-methylpyridin-2-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(245 mg, 0.520 mmol) was deprotected and converted to thedihydrochloride salt according to the procedure of Example 30 (steps eand g) to provide the title compound (57 mg, 30%) as a yellow solid: mp295-305° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.76 (d, J=1.8 Hz, 1H), 8.34 (d,J=6.9 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.67 (d,J=8.3 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.17 (dd,J=8.3, 1.8 Hz, 1H), 7.04 (dd, J=7.1, 2.1 Hz, 1H), 4.53 (s, 2H), 3.79 (s,3H), 3.71 (t, J=6.2 Hz, 2H), 3.25 (t, J=6.2 Hz, 2H), 2.61 (s, 3H); ESIMS m/z 371 [M+H]⁺; HPLC (Method B) 97.3% (AUC), t_(R)=10.9 min.

Example 92 Preparation of1-(5-Methyl-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onedihydrochloride a) 2′-Methoxy-6-methyl-3,4′-bipyridine

2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g,16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol) were reactedaccording to Example 31 (step a) to provide the title compound (2.1 g,98%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, J=2.1 Hz, 1H),8.23 (d, J=5.4 Hz, 1H), 7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1,1H), 7.08 (dd, J=5.4, 1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H),2.61 (s, 3H).

b) 4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one

2′-Methoxy-6-methyl-3,4′-bipyridine (2.1 g, 10.4 mmol) was reactedaccording to Example 31 (step c) to provide the title compound (1.36 mg,68%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.65 (s, 1H) 8.78(d, J=2.1 Hz, 1H), 8.01 (dd, J=8.1, 2.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 1H),7.36 (d, J=8.1, 1H), 6.66 (d, J=1.4 Hz, 1H), 6.55 (dd, J=6.9, 1.8 Hz,1H), 2.51 (s, 3H).

c) tert-Butyl5-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) andtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(294 mg, 0.805 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (220 mg, 58%) as a yellow/greensolid: ¹H NMR (500 MHz, CDCl₃) δ 8.79 (d, J=8.2 Hz, 1H), 7.83 (dd,J=8.1, 2.4 Hz, 1H), 7.56-7.51 (m, 2H), 7.37 (d, J=1.4 Hz, 1H), 7.30 (1H,partially under solvent), 7.08 (d, J=8.7 Hz, 1H), 6.90 (d, J=1.6 Hz,1H), 6.50 (dd, J=7.1, 1.9 Hz, 1H), 4.66 (br s, 2H), 3.85 (br m, 2H),3.65 (s, 3H), 2.84 (br m, 2H), 2.64 (s, 3H), 1.51 (s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl5-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(220 mg, 0.47 mmol) was deprotected and converted to the dihydrochloridesalt according to the procedure of Example 30 (steps e and g) to providethe title compound (50.2 mg, 29%) as a yellow solid: mp 295-305° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.80 (d, J=2.2 Hz, 1H), 8.12 (dd, J=8.1, 2.5 Hz,1H), 7.79 (d, J=7.0 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz,1H), 7.47 (d, J=8.2 Hz, 1H), 7.10 (dd, J=8.3, 1.9 Hz, 1H), 6.93 (d,J=1.8 Hz, 1H), 6.85 (dd, J=7.1, 2.0 Hz, 1H), 4.34 (s, 2H), 3.73 (s, 3H),3.52 (t, J=6.1 Hz, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.62 (s, 3H); ESI MS m/z371 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=8.7 min.

Example 93 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl9-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) andtert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(294 mg, 0.805 mmol) were reacted following the procedure of Example 30(step g) to provide the title compound (208 mg, 55%) as a yellow/greensolid: ¹H NMR (300 MHz, CDCl₃) δ 8.79 (d, J=8.2 Hz, 1H), 7.83 (dd,J=8.0, 2.3 Hz, 1H), 7.58-7.51 (m, 2H), 7.36 (s, 1H), 7.30 (1H, partiallyunder solvent), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 6.90 (d, J=1.7 Hz, 1H),6.50 (dd, J=7.1, 2.0 Hz, 1H), 4.65 (br s, 2H), 3.76 (br m, 2H), 3.65 (s,3H), 2.82 (br m, 2H), 2.64 (s, 3H), 1.52 (s, 9H).

b)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl9-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(208 mg, 0.442 mmol) was deprotected and converted to thedihydrochloride salt according to the procedure of Example 30 (steps eand g) to provide the title compound (40.6 mg, 23%) as a yellow solid:mp 305-313° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.80 (d, J=8.1 Hz, 1H), 8.11(dd, J=8.2, 2.5 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H),7.52 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.11 (dd, J=8.3, 1.8 Hz,1H), 6.93 (d, J=1.9 Hz, 1H), 6.85 (dd, J=7.1, 2.0 Hz, 1H), 4.40 (s, 2H),3.71 (s, 3H), 3.46 (t, J=5.9 Hz, 2H), 3.04 (t, J=5.9 Hz, 2H), 2.62 (s,3H); ESI MS m/z 371 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=8.9 min.

Example 94 Preparation of4-(Benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-bromo-1,9-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate

To a solution of 2-(6-bromo-1H-indol-3-yl)ethanamine (1.9 g, 8.0 mmol)in THF (30 mL) at 0° C. was added saturated aqueous NaHCO₃ (30 mL) andacetyl chloride (0.56 mL, 7.95 mmol). The reaction was warmed up to roomtemperature and stirred at room temperature until complete. The solutionwas concentrated, and the residue was dissolved in CH₂Cl₂, washed withH₂O and brine and dried with Na₂SO₄. The organic solution was filteredand concentrated to give a pale yellow foam. The foam was suspended inbenzene (70 mL) and treated with POCl₃ (3.52 mL, 38.4 mmol). Thereaction was heated and stirred at 85° C. for one hour. After thesolution was concentrated, the residue was purified by flash columnchromatography (silica gel, 10% CH₃OH in CH₂Cl₂) to give a brown solid(1.83 g 91%). The solid was suspended in EtOH (20 mL) and CHCl₃ (20 mL)and cooled to 0° C. NaBH₄ (0.26 g, 6.95 mmol) was added, and thereaction was stirred from 0° C. to room temperature for one hour. Thereaction was quenched with H₂O, extracted with CH₂Cl₂, washed with H₂Oand brine and dried over Na₂SO₄. The organic solution was filtered andconcentrated to give a yellow foam (1.44 g, 78%). The foam was dissolvedin i-PrOH (15 mL) and H₂O (10 mL) and treated with Boc₂O (1.36 g, 6.24mmol) and K₂CO₃ (0.86 g, 6.2 mmol). The reaction was stirred at roomtemperature for one hour and then concentrated under reduced pressure.The resulting residue was dissolved in CH₂Cl₂, washed with H₂O and brineand dried over Na₂SO₄. After filtration and concentration, the residuewas purified by flash column chromatography (silica gel, hexanes/EtOAc,4:1) to give a yellow foam (0.92 g, 46%). The foam was dissolved in DMF(6 mL) and cooled to 0° C. The solution was treated with NaH (60% weightdispersion in mineral oil, 108 mg, 2.68 mmol) followed by CH₃I (0.17 mL,0.69 mmol). The reaction was stirred at 0° C. until complete. Thereaction was quenched with H₂O, extracted with CH₂Cl₂, washed with H₂Oand brine and dried over Na₂SO₄. The organic solution was filtered andconcentrated, and the residue was purified by flash columnchromatography (silica gel, hexanes/EtOAc, 4:1) to give the titlecompound as a white foam (0.82 g, 89%). ¹H NMR (300 MHz, CDCl₃) δ 7.42(s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 5.43-5.20 (m,1H), 4.48-4.26 (m, 1H), 3.62 (s, 3H), 3.24-3.13 (m, 1H), 2.78-2.66 (m,2H), 1.49 (s, 9H), 1.47 (d, J=6.5 Hz, 3H); MS (ESI) m/z 380 [M+H]⁺.

b)4-(Benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a mixture of tert-butyl7-bromo-1,9-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate(0.57 g, 1.6 mmol), 4-(benzyloxy)pyridin-2(1H)-one (0.32 g, 1.6 mmol),8-hydroxyquilinine (46 mg, 0.32 mmol), K₂CO₃ (0.26 g, 1.9 mmol) and CuI(0.15 g, 0.79 mmol) was added DMSO (4 mL). The reaction mixture wasdegassed and back-filled with N₂. The reaction was stirred at 130° C.overnight. The mixture was cooled and filtered through a layer ofCelite. The filtrate was diluted with CH₂Cl₂, washed with H₂O and 5%aqueous LiCl and dried over Na₂SO₄. The organic solution was filteredand concentrated. The residue was purified by flash columnchromatography (silica gel, 5% CH₃OH in CH₂Cl₂) to give a yellow solid(0.5 g, 64%). The solid was dissolved in CH₃OH (8 mL) and treated with 1N HCl in Et₂O (5 mL). The reaction was stirred at room temperature untilcomplete. The solvent was removed under reduced pressure and theresulting solid was dried under vacumn to give the title compound (0.44g, 100%) as a yellow powder: ¹H NMR (500 MHz, CD₃OD) δ 7.79 (d, J=7.0Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.48-7.36 (m, 5H), 7.10(d, J=8.5 Hz, 1H), 6.55 (d, J=6.5 Hz, 1H), 6.33 (s, 1H), 5.27 (s, 2H),4.98 (q, J=6.5 Hz, 1H), 3.76 (s, 3H), 3.67-3.59 (m, 2H), 3.13-3.08 (m,2H), 1.76 (d, J=7.0 Hz, 3H); ESI MS m/z 400 [M+H]⁺; HPLC (Method A)>99%(AUC), t_(R)=12.9 min.

Example 95 Preparation of4-(Benzyloxy)-1-(1,2,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-(benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (205 mg, 0.470 mmol) in CH₃OH (8 mL) was addedformaldehyde (53 μL, 0.71 mmol) and NaBH(OAc)₃ (200 mg, 0.94 mmol). Thereaction was stirred at room temperature until complete and thenconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂and washed with H₂O and 5% aqueous LiCl and dried over Na₂SO₄. Theorganic solution was filtered and concentrated. The residue was purifiedby flash column chromatography (silica gel, 10% CH₃OH in CH₂Cl₂) to give4-(benzyloxy)-1-(1,2,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-oneas a white solid (0.15 g, 77%). The free base was converted to the HClsalt to give the title compound (147 mg, 90%) as an off-white powder: ¹HNMR (500 MHz, CD₃OD) δ 7.58-7.55 (m, 2H), 7.47-7.34 (m, 6H), 6.99 (d,J=8.5, 1.0 Hz, 1H), 6.28 (dd, J=7.5, 2.5 Hz, 1H), 6.11 (d, J=2.5 Hz,1H), 5.18 (s, 2H), 4.27 (q, J=6.5 Hz, 1H), 3.69 (s, 3H), 3.36-3.33 (m,1H), 3.10-2.96 (m, 2H), 2.84-2.80 (m, 1H), 2.65 (s, 3H), 1.51 (d, J=6.5Hz, 3H); ESI MS m/z 414 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=13.0min.

Example 96 Preparation of4-(Benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-(ethoxymethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

To a solution of tert-butyl7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.66 g,1.9 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineraloil, 113 mg, 2.82 mmol) followed by SEMCl (0.50 mL, 2.8 mmol). Thereaction was stirred at room temperature until complete. The reactionwas quenched with H₂O, and the aqueous mixture was extracted withCH₂Cl₂. The organic phase was washed with H₂O and brine and dried overNa₂SO₄. After filtration and concentration, the residue was dried undervacuum to give tert-butyl7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate,which and used directly in the next step. To a mixture of tert-butyl7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.75 g, 1.6 mmol), 4-benzyloxypyridone (0.31 g, 1.6 mmol),8-hydroxyquilinine (34 mg, 0.23 mmol), K₂CO₃ (0.26 g, 1.9 mmol) and CuI(45 mg, 0.23 mmol) was added DMSO (6 mL). The reaction mixture wasdegassed and back-filled with N₂. The reaction was stirred at 130° C.overnight. The mixture was cooled and filtered through a layer ofCelite. The filtrate was diluted with CH₂Cl₂, washed with H₂O and 5%aqueous LiCl and dried over Na₂SO₄. The organic solution was filteredand concentrated, and the residue was purified by flash columnchromatography (silica gel, 5% CH₃OH in CH₂Cl₂) to give the titlecompound as a yellow oil (0.12 g, 13%): ¹H NMR (500 MHz, CDCl₃) δ 7.60(d, J=8.5 Hz, 1H), 7.44-7.37 (m, 6H), 7.31 (d, J=7.5 Hz, 1H), 7.09 (m,1H), 6.12 (s, 1H), 6.07 (d, J=6.5 Hz, 1H), 5.40 (s, 2H), 5.07 (s, 2H),4.65 (m, 2H), 3.86 (m, 2H), 3.51 (t, J=8.0 Hz, 2H), 2.73 (m, 2H), 1.53(s, 9H), 0.89 (t, J=8.0 Hz, 2H), −0.04 (s, 9H); ESI MS m/z 602 [M+H]⁺.

b)4-(Benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a solution of tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-(ethoxymethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(120 mg, 0.20 mmol) in EtOH (2 mL) was added 1 N HCl in Et₂O (1 mL). Thereaction was stirred at 60° C. until complete. The solvent wasconcentrated and the residue was purified by preparative HPLC(Phenomenex Luna C18 (2), 250×50 mm, 15 micron, H₂O with 0.05% TFA andCH₃CN with 0.05% TFA) to give4-(benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-oneas a white solid (54 mg, 73%). The free base was converted to the HClsalt to give the title compound (35 mg, 65%) as a white powder: mp148-149° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s, 2H), 7.66 (d, J=2.0Hz, 1H), 7.59-7.56 (m, 2H), 7.49-7.37 (m, 5H), 7.08-7.05 (m, 1H),6.14-6.12 (m, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.57 (s, 2H), 5.17 (s, 2H),4.38 (m, 2H), 3.55 (m, 2H), 3.45-3.40 (m, 2H), 3.13 (m, 2H), 1.08-1.05(m, 3H); ESI MS m/z 430 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=12.8min.

Example 97 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenylpyridin-2(1H)-onehydrochloride a) tert-Butyl5-methyl-7-(2-oxo-4-(trifluoromethylsulfonyloxy)pyridine-1(2H)-yl)3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

To a solution of tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.98 g, 2.0 mmol) in CH₃OH (30 mL) was added 5% Pd/C (0.3 g) andammonium formate (0.32 g, 5.1 mmol) under an atmosphere of argon. Thereaction was stirred at 90° C. until complete. The reaction mixture wascooled and filtered through a layer of Celite. The solvent was removedunder reduced pressure to give tert-butyl7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate,which was used directly in the next step. To a solution of tert-butyl7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(800 mg, 2.02 mmol) in THF (10 mL) was added LiN(SiMe₃)₂ (1.0 M in THF,2.6 mL, 2.6 mmol) followed by PhN(Tf)₂ (0.94 g, 2.6 mmol) under anatmosphere of argon. The reaction was stirred at room temperature untilcomplete. The solvent was removed under reduced pressure, and theresidue was purified by flash column chromatography (silica gel,hexanes/EtOAc, 1:1) to give the title compound (0.42 g, 40% yield) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 7.57-7.53 (m, 2H), 7.30 (d, J=1.5Hz, 1H), 7.02-6.99 (m, 1H), 6.60 (d, J=2.7 Hz, 1H), 6.27 (dd, J=7.8, 2.7Hz, 1H), 4.65 (s, 2H), 3.85 (m, 2H), 3.65 (s, 3H), 2.84 (m, 2H), 1.51(s, 9H); ESI MS m/z 528 [M+H]⁺.

b)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenylpyridin-2(1H)-onehydrochloride

Following the procedure of Example 25 (step b), but substitutingphenylboronic acid for 4-fluorophenylboronic acid and eliminating themethylation step, the title compound (37 mg, 46%) was obtained as ayellow solid: mp 275-280° C. (decompose); ¹H NMR (500 MHz, DMSO-d₆) δ9.26 (s, 2H), 7.79 (dd, J=8.0, 1.5 Hz, 2H), 7.75 (d, J=7.5 Hz, 1H), 7.62(d, J=1.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.55-7.50 (m, 3H), 7.10 (dd,J=8.5, 2.0 Hz, 1H), 6.78 (d, J=1.5 Hz, 1H), 6.70 (dd, J=7.0, 2.0 Hz,1H), 4.37 (m, 2H), 3.71 (s, 3H), 3.54-3.53 (m, 2H), 3.10 (t, J=6.0 Hz,2H); ESI MS m/z 356 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=12.3 min.

Example 98 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenylpyridin-2(1H)-onehydrochloride

Following the procedure of Example 25 (step b), but substitutingphenylboronic acid for 4-fluorophenylboronic acid, the title compound(56 mg, 83%) was obtained as an off-white solid: mp 290-295° C.(decompose); ¹H NMR (500 MHz, DMSO-d₆) δ 10.46 (s, 1H), 7.80-7.74 (m,3H), 7.63 (s, 1H), 7.56-7.52 (m, 4H), 7.11 (d, J=8.0 Hz, 1H), 6.78 (s,1H), 6.70 (d, J=7.0 Hz, 1H), 4.68-4.65 (m, 1H), 4.34-4.30 (m, 1H),3.82-3.79 (m, 1H), 3.71 (s, 3H), 3.53-3.51 (m, 1H), 3.20 (m, 2H), 3.00(d, J=4.0 Hz, 3H); ESI MS m/z 370 [M+H]⁺; HPLC (Method A) 98% (AUC),t_(R)=12.5 min.

Example 99 Preparation of4-(2-Fluoro-4-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 25 (step b), but substituting2-fluoro-4-methoxyphenylboronic acid for 4-fluorophenylboronic acid andeliminating the methylation step, the title compound (34 mg, 19%) wasobtained as a green powder: mp 270-274° C.; ¹H NMR (500 MHz, CD₃OD) δ7.72 (d, J=7.0 Hz, 1H), 7.63-7.56 (m, 3H), 7.14 (dd, J=8.5, 1.5 Hz, 1H),6.92 (dd, J=8.5, 2.5 Hz, 1H), 6.87 (dd, J=13.0, 2.5 Hz, 1H), 6.84 (s,1H), 6.77-6.75 (m, 1H), 4.50 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 3.68(t, J=6.0 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H); ESI MS m/z 404 [M+H]⁺; HPLC(Method A)>99% (AUC), t_(R)=12.3 min

Example 100 Preparation of1-(2-Acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(benzyloxy)pyridin-2(1H)-one

To a solution of4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(0.2 g, 0.5 mmol) in CH₂Cl₂ (6 mL) was added triethylamine (0.20 mL, 1.4mmol) followed by acetyl chloride (50 μL, 0.71 mmol). The reaction wasstirred at room temperature until complete. After the solvent wasremoved under reduced pressure, the residue was purified by flash columnchromatography (silica gel, 5% CH₃OH in CH₂Cl₂) to give the titlecompound (72.2 mg, 36%) as a yellow solid and as a mixture of rotamers:mp 225-230° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.53-7.36 (m, 6H), 7.32-7.30(m, 2H), 7.06-7.00 (m, 1H), 6.09 (d, J=3.0 Hz, 1H), 6.07-6.04 (m, 1H),5.06 (s, 2H), 4.82 (s, 1H), 4.67 (s, 1H), 4.03 (t, J=5.5 Hz, 1H), 3.84(t, J=5.5 Hz, 1H), 3.64 (s, 3H), 2.90 (t, J=5.5 Hz, 1H), 2.84 (t, J=5.5Hz, 1H), 2.24, 2.22 (2×s, 3H); ESI MS m/z 428 [M+H]⁺; HPLC (Method A)95.7% (AUC), t_(R)=16.8 min.

Example 101 Preparation of1-(2-Acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one

Following the procedure of Example 100, but substituting4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-pyridin-2(1H)-onefor4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one,the title compound (71 mg, 61%) was obtained as a yellow solid and as amixture of rotamers: mp 220-224° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d,J=1.5 Hz, 1H), 7.54-7.46 (m, 3H), 7.35 (d, J=7.5 Hz, 1H), 7.32 (d, J=2.0Hz, 1H), 7.03 (ddd, J=20, 8.0, 1.5 Hz, 1H), 6.15-6.08 (m, 2H), 5.18 (s,2H), 4.83, 4.70 (2×s, 2H), 4.04 (t, J=5.5 Hz, 1H), 3.85 (t, J=5.5 Hz,1H), 3.65, 3.64 (2×s, 3H), 2.91 (t, J=5.5 Hz, 1H), 2.85 (t, J=5.5 Hz,1H), 2.23, 2.25 (2×s, 3H); ESI MS m/z 447 [M+H]⁺; HPLC (Method A) 96.4%(AUC), t_(R)=14.5 min.

Example 102 Preparation of4-(Cyclohexylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(Cyclohexylmethoxy)pyridin-2(1H)-one

To a solution of cyclohexylmethanol (1.1 mL, 9.3 mmol) in DMF (8 mL) wasadded NaH (60% weight dispersion in mineral oil, 0.37 g, 9.3 mmol) inone portion. After the bubbles disappeared, 4-chloropyridine N-oxide(1.0 g, 7.7 mmol) was added. The reaction was stirred at roomtemperature under Ar until complete. The reaction was quenched withwater and the aqueous mixture was extracted with CH₂Cl₂. The combinedorganic extracts were washed with H₂O and 5% aqueous LiCl and dried overNa₂SO₄. After filtration and concentration, the residue was purified byflash column chromatography (silica gel, 10% CH₃OH in CH₂Cl₂) to give ayellow solid. The yellow solid was suspended in Ac₂O (5 mL) and heatedat 140° C. for 4 h. The reaction mixture was cooled, diluted withCH₃OH/H₂O (10 mL, 1:1) and stirred at room temperature for 1 h. Themixture was concentrated, and the residue was purified by flash columnchromatography (silica gel, 10% CH₃OH in CH₂Cl₂) to give the titlecompound (0.92 g, 58%) as a brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.03 (s, 1H), 7.21 (d, J=7.2 Hz, 1H), 5.83 (dd, J=7.2, 2.4 Hz, 1H),5.64 (d, J=2.4 Hz, 1H), 3.72 (d, J=6.0 Hz, 2H), 1.84-1.68 (m, 6H),1.30-1.01 (m, 5H).

Following the procedure of Example 1 (steps c and d), but substituting4-(cyclohexylmethoxy)pyridin-2(1H)-one for 4-benzyloxypyridone, thetitle compound (56 mg, 81%) was obtained as a yellow solid: mp 256-260°C.; ¹H NMR (500 MHz, CD₃OD) δ 7.67-7.65 (m, 2H), 7.50 (s, 1H), 7.09 (d,J=8.5 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H), 6.10 (s, 1H), 4.58 (s, 2H), 3.92(d, J=5.5 Hz, 2H), 3.75 (s, 3H), 3.63 (t, J=6.0 Hz, 2H), 3.15 (d, J=6.0Hz, 2H), 1.92-1.74 (m, 6H), 1.39-1.19 (m, 5H); ESI MS m/z 392 [M+H]⁺;HPLC (Method A) 97.8% (AUC), t_(R)=14.4 min.

Example 103 Preparation of4-(Cyclohexylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 102, but substituting substitutingtert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylatefor tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate,the title compound (197 mg, 100%) was obtained as a pale green solid: mp245-250° C. (decompose); ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 2H), 7.55(d, J=8.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.50 (s, 1H), 6.99 (dd,J=8.5, 1.5 Hz, 1H), 6.04 (dd, J=7.5, 2.5 Hz, 1H), 5.85 (d, J=2.5 Hz,1H), 4.35 (s, 2H), 3.82 (d, J=6.0 Hz, 2H), 3.68 (s, 3H), 3.54-3.53 (m,2H), 3.09 (t, J=5.5 Hz, 2H), 1.80-1.65 (m, 6H), 1.30-1.01 (m, 5H); ESIMS m/z 392 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=14.3 min.

Example 104 Preparation of4-(Cyclohexylmethoxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-(cyclohexylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (110 mg, 0.26 mmol) in CH₃OH (5 mL) was addedtriethylamine (90 μL, 2.5 mmol), formaldehyde (30 μL, 0.39 mmol) andNaBH(OAc)₃ (110 mg, 0.52 mmol). The reaction was stirred at roomtemperature until complete. The solvent was removed under reducedpressure, and the residue was dissolved in CH₂Cl₂. The organic solutionwas washed with H₂O and 5% aqueous LiCl and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by flash columnchromatography (silica gel, 10% CH₃OH in CH₂Cl₂) to give4-(cyclohexylmethoxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-oneas a white solid (73 mg, 69%). The free base was converted to the HClsalt to give the title compound (84 mg, 100%) as a white powder: mp270-272° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.53 (s, 1H), 7.53 (d, J=7.5Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.00 (dd,J=8.5, 1.5 Hz, 1H), 6.04 (dd, J=7.5, 2.5 Hz, 1H), 5.85 (d, J=3.0 Hz,1H), 4.64 (d, J=13 Hz, 1H), 4.30 (dd, J=14, 7.5 Hz, 1H), 3.82 (d, J=6.0Hz, 2H), 3.80-3.78 (m, 1H), 3.69 (s, 3H), 3.51-3.47 (m, 1H), 3.18 (t,J=5.5 Hz, 2H), 2.98 (d, J=4.5 Hz, 3H), 1.80-1.65 (m, 6H), 1.30-1.01 (m,5H); ESI MS m/z 406 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=14.4 min.

Example 105 Preparation of4-(Benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a)7-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid

Glyoxylic acid monohydrate (3.69 g, 40.1 mmol) was added to a solutionof a 2:1 mixture of 2-(6-bromo-1H-indol-3-yl)ethanamine and2-(4-bromo-1H-indol-3-yl)ethanamine (7.38 g, 30.9 mmol) in 0.4 N HCl (50mL), and the resulting solution was stirred at 25° C. for 30 min. Thesolution was adjusted to pH 3.5 with 6 N NaOH solution, and theresulting tan suspension was stirred at 25° C. for 22 h. The suspensionwas adjusted to pH 5 with 6 N NaOH solution, and the resultingsuspension was filtered. The filtered solid was dried under reducedpressure to afford 3.85 g (42%) of a 2:1 mixture of the title compoundand an undesired regioisomer as a tan solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.90 (s, 1H), 9.00 (br s, 1H), 7.63 (s, 1H), 7.33 (d, J=8.4 Hz, 1H),7.12-7.04 (m, 1H), 4.66 (s, 1H), 3.50-2.70 (m, 4H).

Undesired regioisomer: ¹H NMR (300 MHz, DMSO-d₆) δ 11.09 (s, 1H), 9.00(br s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.12-7.04 (m, 1H), 6.91 (overlappingdd, J=8.0 Hz, 1H), 4.66 (s, 1H), 3.50-2.70 (m, 4H).

b)7-Bromo-1-((tert-butyldimethylsilyloxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

A 1.0 M solution of LiAlH₄ in THF (26 mL, 26.1 mmol) was added to asolution of a 2:1 mixture of7-bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid andthe undesired regioisomer (3.85 g, 13.1 mmol) in THF (50 mL) under N₂,and the resulting solution was heated at reflux for 1 h. The solutionwas cooled to 0° C. and H₂O, 6 N NaOH in H₂O and H₂O were addedcarefully in succession. The resulting suspension was filtered throughcelite. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded2.48 g of a tan foam. Et₃N (6.2 mL, 44.3 mmol) was added to a suspensionof TBSCl (6.68 g, 44.3 mmol) and the above tan foam in CH₂Cl₂ (50 mL)under N₂, and the resulting suspension was stirred at 25° C. overnight.H₂O was added to the suspension, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 Et₂O/MeOH/NH₄OH), 100:0 to 75:25) yielded thetitle compound (1.186 g, 32%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ8.50 (s, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.18 (dd,J=8.4, 1.7 Hz, 1H), 4.19-4.10 (m, 1H), 3.92 (dd, J=9.2, 5.0 Hz, 1H),3.69 (dd, J=9.2, 9.2 Hz, 1H), 3.32 (ddd, J=12.6, 4.2, 4.2 Hz, 1H),3.11-3.01 (m, 1H), 2.75-2.62 (m, 2H), 0.97 (s, 9H), 0.13 (s, 6H).

c) tert-Butyl7-bromo-1-((tert-butyldimethylsilyloxy)methyl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

Boc₂O (752 mg, 3.45 mmol) was added to a suspension of7-Bromo-1-((tert-butyldimethyl-silyloxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1.239 g, 3.14 mmol) and K₂CO₃ (476 mg, 3.45 mmol) in a 1:1 mixture ofH₂O/i-PrOH (80 mL), and the resulting suspension was stirred at 25° C.for 2 h. The suspension was filtered, and the solid was concentratedunder reduced pressure. MeI (0.19 mL, 3.1 mmol) was added to asuspension of the above solid and Cs₂CO₃ (1.34 g, 4.12 mmol) in DMSO (20mL) under N₂, and the resulting suspension was stirred at 25° C. for 4h. H₂O was added to the suspension, and the resulting suspension wasfiltered. The solid was dried under reduced pressure to afford the titlecompound (728 mg, 46%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.44(br s, 1H), 7.37-7.28 (m, 1H), 7.23-7.15 (m, 1H), 5.49-5.43 (m, 0.6H),5.37-5.32 (m, 0.4H), 4.56-4.48 (m, 0.4H), 4.35-4.24 (m, 0.6H), 3.98-3.84(m, 2H), 3.68 (s, 3H), 3.43-3.35 (m, 0.6H), 3.30-3.21 (m, 0.4H),2.90-2.75 (m, 1H), 2.72-2.63 (m, 1H), 1.50 (s, 9H), 0.90-0.82 (m, 9H),0.14-0.02 (m, 6H).

d)4-(Benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

A suspension of tert-butyl7-bromo-1-((tert-butyldimethylsilyloxy)methyl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(727 mg, 1.47 mmol), 4-(benzyl-oxy)pyridin-2(1H)-one (591 mg, 2.94mmol), CuI (110 mg, 0.576 mmol), 8-hydroxyquinoline (84 mg, 0.58 mmol)and Cs₂CO₃ (720 mg, 2.21 mmol) in DMSO (10 mL) was degassed underreduced pressure for 45 min. The suspension was put under Ar and heatedat 135° C. with stirring for 14 h. The suspension was cooled, 1:1MeOH/NH₄OH (40 mL) was added, and the resulting suspension was stirredfor 30 min. CH₂Cl₂ was added and the phases were separated. The aqueousphase was extracted with CH₂Cl₂, and the combined organic extracts werewashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 Et₂O/MeOH/NH₄OH) 100:0 to 0:100) afforded theamine as a yellow amorphous solid. A 1.0 M solution of TBAF in THF (0.57mL, 0.57 mmol) was added to a solution of the above yellow semi-solid inTHF (10 mL) under N₂, and the resulting solution was stirred at 25° C.for 1.5 h. H₂O and CH₂Cl₂ were added to the solution and the phases wereseparated. The aqueous phase was extracted with CH₂Cl₂, and the combinedorganic phases were dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 Et₂O/MeOH/NH₄OH) 100:0 to 0:100) yielded ayellow amorphous solid. TFA (2 mL) was added to a solution of the aboveamorphous solid in CH₂Cl₂ (10 mL) under N₂, and the resulting solutionwas stirred at 25° C. for 1 h. The solution was concentrated underreduced pressure. The resulting residue was diluted with CH₂Cl₂ andneutralized with a saturated aqueous NaHCO₃ solution. The phases wereseparated. The organic phase was dried over Na₂SO₄ and concentratedunder reduced pressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) yielded thetitle compound (56 mg, 9%) as a viscous oil: ¹H NMR (500 MHz, CDCl₃) δ7.56 (d, J=8.0 Hz, 1H), 7.46-7.37 (m, 5H), 7.32 (d, J=7.5 Hz, 1H), 7.30(d, J=1.5 Hz, 1H), 7.03 (dd, J=8.0, 1.5 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H),6.06 (dd, J=7.5, 2.5 Hz, 1H), 5.08 (s, 2H), 4.14 (dd, J=10.0, 4.5 Hz,1H), 3.80 (dd, J=10.0, 4.5 Hz, 1H), 3.69-3.62 (m, 4H), 3.23 (ddd,J=14.0, 4.5, 4.5 Hz, 1H), 3.12-3.05 (m, 1H), 2.78-2.73 (m, 2H); ESI MSm/z 416 [M+H]⁺.

e)4-(Benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

A 1.0 M solution of HCl in Et₂O (0.13 mL, 0.13 mmol) was added to asolution of4-(benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(55 mg, 0.13 mmol) in CH₂Cl₂ (10 mL) under N₂ and stirred at 25° C. for1 h. The solution was concentrated to afford the title compound (32 mg,54%) as an off-white powder: mp 168-170° C.; ¹H NMR (500 MHz, DMSO-d₆) δ9.48 (br s, 1H), 9.10 (br s, 1H), 7.56 (overlapping dd, J=8.5 Hz, 2H),7.52 (s, 1H), 7.49-7.41 (m, 4H), 7.40-7.36 (m, 1H), 7.01 (dd, J=7.0, 1.5Hz, 1H), 6.12 (dd, J=7.5, 1.5 Hz, 1H), 5.98 (d, J=1.5 Hz, 1H), 5.72 (t,J=3.3 Hz, 1H), 5.16 (s, 2H), 4.89-4.82 (m, 1H), 4.07-4.01 (m, 1H),3.80-3.71 (m, 1H), 3.72 (s, 3H), 3.61-3.50 (m, 1H), 3.49-3.43 (m, 1H),3.02-2.94 (m, 2H); ESI MS m/z 416 [M+H]⁺.

Example 106 Preparation of4-(Benzyloxy)-1-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

A suspension of 4-(benzyloxy)pyridin-2(1H)-one (426 mg, 2.12 mmol),tert-butyl7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(1.28 g, 2.54 mmol), CuI (484 mg, 2.54 mmol), 8-hydroxyquinoline (369mg, 2.54 mmol) and Cs₂CO₃ (760 mg, 2.33 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underAr and heated at 135° C. with stirring for 1.5 h. The suspension wascooled, 4:1 CH₂Cl₂/(9:1 MeOH/NH₄OH) (50 mL) was added and the resultingsuspension was stirred at 25° C. for 10 min. The suspension was passedthrough a plug of silica gel and the filtrate was washed with brine. Thesolution was dried over Na₂SO₄ and concentrated under reduced pressureto afford an amorphous solid. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) yielded thetitle compound (715 mg, 54%) as an off-white solid: ¹H NMR (300 MHz,CDCl₃) δ 8.18 (br s, 1H), 7.82-7.73 (m, 2H), 7.48-7.35 (m, 6H),7.33-7.23 (m, 4H), 6.12-5.97 (m, 2H) 5.07 (s, 2H), 4.90 (br s, 2H),3.72-3.64 (m, 2H), 2.73-2.63 (m, 2H), 2.34 (s, 3H), 1.51 (s, 9H).

b)4-(Benzyloxy)-1-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

TFA (2 mL) was added to a solution of tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(678 mg, 1.09 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andEtOAc were added, and the phases were separated. The aqueous phase wasextracted with CH₂Cl₂, and the combined organic phases were dried overNa₂SO₄. The organic solution was concentrated under reduced pressure toafford 510 mg of an off-white solid. NaOH (469 mg, 11.7 mmol) was addedto a solution of the off-white solid (123 mg) in CH₂Cl₂/MeOH (10 mL)that had been degassed with N₂. The resulting solution was heated at 40°C. with stirring for 5 h under N₂. The solution was allowed to cool,saturated NH₄Cl solution and CH₂Cl₂ were added, and the phases wereseparated. The organic phase was washed with saturated NaHCO₃ solution,dried over Na₂SO₄ and concentrated under reduced pressure to yield anoff-white solid. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) afforded awhite solid. 1 M HCl in Et₂O (0.28 ml, 0.28 mmol) was added to asolution of the white solid in CH₂Cl₂ (10 mL) under N₂, and theresulting solution was stirred at 25° C. for 30 min. The resultingsuspension was filtered. The solid was washed with CH₂Cl₂ and driedunder reduced pressure to afford the title compound (26 mg, 24%) as awhite solid: mp 246-248° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.22 (s, 1H),9.29 (br s, 2H), 7.54 (dd, J=12.0, 8.0 Hz, 2H), 7.50-7.41 (m, 4H),7.40-7.33 (m, 2H), 6.96 (dd, J=8.0, 1.5 Hz, 1H), 6.09 (dd, J=7.5, 2.5Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.38 (s, 2H), 3.50-3.42(m, 2H) 3.00-2.92 (m, 2H); ESI MS m/z 372 [M+H]⁺.

Example 107 Preparation of4-(Benzyloxy)-1-(2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a)4-(Benzyloxy)-1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

TFA (2 mL) was added to a solution of tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(678 mg, 1.09 mmol) in CH₂Cl₂ (10 mL) under N₂ and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andEtOAc were added to the solution and the phases were separated. Theaqueous phase was extracted with CH₂Cl₂ and the combined organic phaseswere dried over Na₂SO₄. The organic solution was concentrated underreduced pressure to afford 510 mg of an off-white solid. Formaldehyde(37% in H₂O, 0.04 mL, 0.49 mmol) was added to a solution of theoff-white solid (170 mg) in 1:1 MeOH/CH₂Cl₂ (10 mL) and the resultingsolution was stirred at 25° C. for 45 min. NaBH(OAc)₃ (137 mg, 0.648mmol) was added to the solution and the resulting suspension was stirredat 25° C. for 30 min. The suspension was concentrated under reducedpressure and the resulting residue was diluted with CH₂Cl₂ and saturatedNaHCO₃ solution. The phases were separated. The organic phase was driedover Na₂SO₄ and concentrated under reduced pressure to yield the titlecompound (174 mg, 89%) as a viscous oil: ¹H NMR (300 MHz, CDCl₃) δ 8.14(d, J=1.5 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.47-7.35 (m, 6H), 7.33-7.28(m, 1H), 7.26-7.21 (m, 3H), 6.12-6.05 (m, 2H), 5.07 (s, 2H), 3.92 (br s,2H), 2.79-2.70 (m, 4H), 2.56 (s, 3H), 2.33 (s, 3H).

b)4-(Benzyloxy)-1-(2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

NaOH (644 mg, 16.1 mmol) was added to a solution of the4-(benzyloxy)-1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(174 mg, 0.322 mmol) in CH₂Cl₂/MeOH (10 mL) that had been degassed withN₂. The resulting solution was heated at reflux with stirring for 2 hunder N₂. The solution was allowed to cool, saturated NH₄Cl solution andCH₂Cl₂ were added, and the phases were separated. The organic phase waswashed with saturated NaHCO₃ solution, dried over Na₂SO₄ andconcentrated under reduced pressure to yield a white solid. 1 M HCl inEt₂O (0.38 ml, 0.38 mmol) was added to a solution of the white solid in9:1 CH₂Cl₂/MeOH (10 mL) under N₂, and the resulting solution was stirredat 25° C. for 30 min. The solution was concentrated, and the residue wasdiluted with a small amount of CH₂Cl₂/CH₃CN. The resulting suspensionwas filtered, and the solid was dried under reduced pressure to yieldthe title compound (46 mg, 34%) as a white solid: mp 168-170° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 11.30 (s, 1H), 10.50-10.41 (m, 1H), 7.58-7.52 (m,2H), 7.49-7.40 (m, 4H), 7.39-7.35 (m, 2H), 6.96 (br d, J=8.0 Hz, 1H),6.09 (br d, J=7.5 Hz, 1H), 5.97 (br s, 1H), 5.15 (s, 2H), 4.60 (br d,J=15.0 Hz, 1H), 4.41 (dd, J=15.0, 7.5 Hz, 1H), 3.78-3.71 (m, 1H),3.45-3.38 (m, 1H), 3.09-2.98 (m, 5H); ESI MS m/z 386 [M+H]⁺.

Example 108 Preparation of1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoro-methyl)phenyl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

A suspension of 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (121 mg,0.504 mmol), tert-butyl7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(305 mg, 0.605 mmol), CuI (115 mg, 0.605 mmol), 8-hydroxyquinoline (88mg, 0.605 mmol) and Cs₂CO₃ (181 mg, 0.605 mmol) in DMSO (5 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underAr and heated at 135° C. with stirring for 2.5 h. The suspension wascooled, 4:1 CH₂Cl₂/(9:1 MeOH/NH₄OH) (25 mL) was added and the resultingsuspension was stirred at 25° C. for 10 min. The suspension was passedthrough a plug of silica gel and the filtrate was washed with brine. Thesolution was dried over Na₂SO₄ and concentrated under reduced pressureto afford an amorphous solid. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) gave thetitle compound (170 mg, 51%) as a pink foam: ¹H NMR (300 MHz, CDCl₃) δ8.26 (br s, 1H), 7.83-7.74 (m, 6H), 7.53 (d, J=7.2 Hz, 1H), 7.51-7.45(m, 1H), 7.35-7.23 (m, 3H), 6.93 (d, J=1.8 Hz, 1H), 6.54 (dd, J=7.2, 1.8Hz, 1H), 4.91 (br s, 2H), 3.75-3.65 (m, 2H), 2.73-2.68 (m, 2H), 2.36 (s,3H), 1.52 (s, 9H).

b)1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

TFA (1 mL) was added to a solution of tert-butyl7-(2-oxo-4-(4-(trifluoro-methyl)phenyl)pyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(170 mg, 0.256 mmol) in CH₂Cl₂ (5 mL) under N₂, and the resultingsolution was stirred at 25° C. for 30 min. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure to afford 145 mg of a pink solid. NaOH (227 mg, 5.67 mmol) wasadded to a solution of the pink solid (64 mg) in CH₂Cl₂/MeOH (10 mL)that had been degassed with N₂. The resulting solution was heated atreflux with stirring for 7 h under N₂. The solution was allowed to cool,saturated NH₄Cl solution and CH₂Cl₂ were added, and the phases wereseparated. The organic phase was washed with saturated NaHCO₃ solution,dried over Na₂SO₄ and concentrated under reduced pressure to yield ayellow powder. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) afforded ayellow solid. 1 M HCl in Et₂O (0.07 ml, 0.06 mmol) was added to asolution of the yellow solid in 9:1 CH₂Cl₂/MeOH (10 mL) under N₂ and theresulting solution was stirred at 25° C. for 30 min. The solution wasconcentrated under reduced pressure to yield the title compound (27 mg,54%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H), 9.21(br s, 2H), 8.01 (d J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.80 (d,J=7.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.07 (dd,J=8.0, 1.5 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.72 (dd, J=7.0, 2.0 Hz,1H), 4.40 (s, 2H), 3.52-3.48 (m, 2H), 2.99 (t, J=6.0 Hz, 2H); ESI MS m/z410 [M+H]⁺.

Example 109 Preparation of1-(2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoro-methyl)phenyl)pyridin-2(1H)-onehydrochloride a)1-(2-Methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one

TFA (1 mL) was added to a solution of tert-butyl7-(2-oxo-4-(4-(trifluoro-methyl)phenyl)pyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(170 mg, 0.256 mmol) in CH₂Cl₂ (5 mL) under N₂, and the resultingsolution was stirred at 25° C. for 30 min. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure to afford 145 mg of a pink solid. Formaldehyde (37% in H₂O,0.02 mL, 0.2 mmol) was added to a solution of the pink solid (80 mg) in1:1 MeOH/CH₂Cl₂ (4 mL) and the resulting solution was stirred at 25° C.for 45 min. NaBH(OAc)₃ (60 mg, 0.28 mmol) was added to the solution andthe resulting suspension was stirred at 25° C. for 30 min. Thesuspension was concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂ and saturated NaHCO₃ solution. The phases wereseparated. The organic phase was dried over Na₂SO₄ and concentratedunder reduced pressure to yield the title compound (61 mg, 74%) as apink foam: ¹H NMR (300 MHz, CDCl₃) δ 8.23 (d, J=1.8 Hz, 1H), 7.79-7.71(m, 6H), 7.53 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.32 (dd,J=8.4, 1.8 Hz, 1H), 7.27-7.22 (m, 2H), 6.93 (d, J=1.8 Hz, 1H), 6.53 (dd,J=7.2, 1.8 Hz, 1H), 3.93 (br s, 2H), 2.80-2.60 (m, 4H), 2.57 (s, 3H),2.34 (s, 3H).

b)1-(2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoro-methyl)phenyl)pyridin-2(1H)-onehydrochloride

NaOH (211 mg, 5.28 mmol) was added to a solution of1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one(61 mg, 0.11 mmol) in CH₂Cl₂/MeOH (10 mL) that had been degassed withN₂. The resulting solution was heated at reflux with stirring for 7 hunder N₂. The solution was allowed to cool, saturated NH₄Cl solution andCH₂Cl₂ were added, and the phases were separated. The organic phase waswashed with saturated NaHCO₃ solution, dried over Na₂SO₄ andconcentrated under reduced pressure to yield a yellow solid. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) afforded a yellow solid. 1 M HCl inEt₂O (0.06 ml, 0.06 mmol) was added to a solution of the yellow solid in9:1 CH₂Cl₂/MeOH (10 mL) under N₂ and the resulting solution was stirredat 25° C. for 30 min. The solution was concentrated under reducedpressure to yield the title compound (28 mg, 58%) as a yellow solid: mp200-204° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.36 (s, 1H), 10.35 (br s,1H), 8.02 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.80 (d, J=7.0 Hz,1H), 7.59 (d, J=8.0 Hz, 1H), 7.49 (br s, 1H), 7.07 (dd, J=8.0, 1.5 Hz,1H), 6.87 (d, J=1.5 Hz, 1H), 6.72 (d, J=7.0, 1.5 Hz, 1H), 4.62 (br d,J=16.0 Hz, 1H), 4.49-4.40 (m, 1H), 3.81-3.73 (m, 1H), 3.49-3.39 (m, 1H),3.12-3.00 (m, 5H); ESI MS m/z 424 [M+H]⁺.

Example 110 Preparation of4-(Benzyloxy)-1-(1,1,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a)7-Bromo-1,1-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Concentrated HCl (10 mL) was added to a suspension of a 2:1 mixture of2-(6-bromo-1H-indol-3-yl)ethanamine and2-(4-bromo-1H-indol-3-yl)ethanamine (9.90 g, 41.4 mmol) and Na₂SO₄ (30g) in 1:1 acetone/n-butanol (100 mL). The resulting suspension washeated at 60° C. with stirring for 4 d. The suspension was cooled andconcentrated under reduced pressure. The residue was diluted with EtOAc,and the suspension was filtered. The filtrate was washed with saturateNaHCO₃ solution, dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) yielded thetitle compound (1.68 g, 15%) as a red foam: ¹H NMR (500 MHz, CDCl₃) δ7.66 (br s, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.19(dd, J=8.5, 1.5 Hz, 1H), 3.20 (t, J=5.5 Hz, 2H), 2.68 (t, J=5.5 Hz, 2H),1.47 (s, 6H).

b) tert-Butyl7-bromo-1,1,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

Boc₂O (7.88 g, 36.1 mmol) was added to a suspension of7-bromo-1,1-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.68 g,6.02 mmol) and K₂CO₃ (1.66 g, 12.0 mmol) in 1:1 H₂O/i-PrOH (80 mL), andthe resulting suspension was stirred at 25° C. for 2 h. The suspensionwas filtered. The solid was washed with H₂O and dried under reducedpressure to afford 1.285 g of a white solid. NaH (60% dispersion in oil,152 mg, 3.80 mmol) was added to a solution of the white solid (720 mg)in DMF (10 mL) under N₂ and the resulting suspension was stirred at 25°C. for 30 min. MeI (0.18 mL, 2.9 mmol) was added to the suspension, andthe resulting suspension was stirred at 25° C. for 30 min. Thesuspension was cooled to 0° C., and H₂O was added slowly. Hexanes wasadded and the phases were separated. The organic phase was dried overNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(silica gel, hexanes/(1:1 EtOAc/hexanes) 100:0 to 60:40) yielded thetitle compound (471 mg, 36%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.43 (d, J=1.5 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.4, 1.5 Hz,1H), 3.79-3.72 (m, 5H), 2.73 (t, J=5.4 Hz, 2H), 1.88 (s, 6H), 1.53 (s,9H).

c) tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,1,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

A suspension of 4-(benzyloxy)pyridin-2(1H)-one (107 mg, 0.532 mmol),tert-butyl7-bromo-1,1,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(251 mg, 0.639 mmol), CuI (122 mg, 0.639 mmol), 8-hydroxyquinoline (93mg, 0.639 mmol) and Cs₂CO₃ (190 mg, 0.585 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underAr and heated at 135° C. with stirring overnight. The suspension wascooled, 40:9:1 CH₂Cl₂/MeOH/NH₄OH was added and the resulting suspensionwas stirred at 25° C. for 30 min. The suspension was passed through aplug of silica gel, and the filtrate was washed with brine. The solutionwas dried over Na₂SO₄ and concentrated under reduced pressure to affordan amorphous solid. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 1:1) yielded thetitle compound (74 mg, 27%) as a white powder: ¹H NMR (300 MHz, CDCl₃) δ7.54 (d, J=8.1 Hz, 1H), 7.46-7.35 (m, 4H), 7.33-7.25 (m, 3H), 7.12 (dd,J=8.1, 2.1 Hz, 1H), 6.09 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.5, 2.6 Hz,1H), 5.06 (s, 2H), 3.80 (s, 3H), 3.77 (t, J=4.8 Hz, 2H), 2.77 (t, J=4.8Hz, 2H), 1.89 (s, 6H), 1.54 (s, 9H).

d)4-(Benzyloxy)-1-(1,1,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

TFA (1 mL) was added to a solution of tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,1,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(72 mg, 0.14 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 30 min. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Purification by semi-preparative HPLC (Phenomenex Luna C18(2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05%TFA) afforded 14 mg of clear crystals. 1 M HCl in Et₂O (0.04 ml, 0.04mmol) was added to a solution of the clear crystals in CH₂Cl₂ (10 mL)under N₂ and the resulting solution was stirred at 25° C. for 30 min.The solution was concentrated under reduced pressure to yield the titlecompound (15 mg, 24%) as an off-white powder: mp 296-298; ¹H NMR (500MHz, DMSO-d₆) δ 9.59 (s, 2H), 7.58-7.51 (m, 3H), 7.49-7.41 (m, 4H),7.40-7.35 (m, 1H), 7.01 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.8Hz, 1H), 5.97 (d, J=2.8 Hz, 1H), 5.16 (s, 2H), 3.80 (s, 3H), 3.52-3.48(m, 2H), 2.99 (t, J=6.0 Hz, 2H), 1.81 (s, 6H); ESI MS m/z 414 [M+H]⁺.

Example 111 Preparation of(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidin-2-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) (S)-tert-Butyl2-(bromomethyl)pyrrolidine-1-carboxylate

Beilstein Registry Number 6325435

This compound was prepared in accordance with the procedure of Kawara etal., Tetrahedron Lett., 1994, 35, 8805-8808.

b)(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidin-2-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

A suspension of4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(250 mg, 0.646 mmol), (S)-tert-butyl2-(bromomethyl)pyrrolidine-1-carboxylate (342 mg, 1.29 mmol) and Cs₂CO₃(841 mg, 2.58 mmol) in DMSO (10 mL) under N₂ was stirred at 25° C. for16 h. The suspension was heated at 60° C. for 1 d. The suspension wascooled, and H₂O was added. The suspension was filtered. The solid waswashed with H₂O and dried under reduced pressure. Flash chromatograph(silica gel, hexanes/(9:0.9:0.1 Et₂O/MeOH/NH₄OH), 100:0 to 0:100)afforded 18 mg of a yellow solid. TFA (1 mL) was added to a solution ofthe yellow solid in CH₂Cl₂ (5 mL) under N₂ and the resulting solutionwas stirred at 25° C. for 3.5 h. Saturated NaHCO₃ solution and CH₂Cl₂were added and the phases were separated. The organic phase was driedover Na₂SO₄ and concentrated under reduced pressure. Flash chromatograph(silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1 Et₂O/MeOH/NH₄OH), 100:0 to0:100) yielded 10 mg of a yellow solid. 1 M HCl in Et₂O (0.04 ml, 0.04mmol) was added to a solution of the yellow solid in CH₂Cl₂ (10 mL)under N₂, and the resulting solution was stirred at 25° C. for 30 min.The solution was concentrated under reduced pressure to yield the titlecompound (10 mg, 3%) as an off-white powder: mp 160-162° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.25 (br s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.54-7.40 (m,6H), 7.39-7.34 (m, 1H), 7.04-6.93 (m, 1H), 6.11 (dd, J=7.5, 2.5 Hz, 1H),5.97 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.98-3.45 (m, 1H), 3.39 (s, 1H),3.30-3.21 (m, 2H), 2.25-2.10 (m, 1H), 2.05-1.74 (m, 2H), 1.73-1.60 (m,1H); ESI MS m/z 469 [M+H]⁺.

Example 112 Preparation of4-(4-Chloro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(4-Chloro-2-methoxyphenyl)pyridine 1-oxide

4-Chloropyridine-N-oxide (500 mg, 3.85 mmol),2-methoxy-4-chlorophenylboronic acid (862 mg, 4.63 mmol) and K₂CO₃ (1.59g, 11.55 mmol) were suspended in DMSO (5 mL) and PdCl₂(dppf) (314 mg,0.385 mmol) was added. The reaction mixture was placed under vacuum for20 min and flushed with N₂. This process was repeated, and the reactionmixture was heated at 120° C. for 3 h. The reaction mixture was cooledto 25° C. and partitioned between methylene chloride and 5% lithiumchloride. The aqueous phase was removed, and the organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated todryness under reduced pressure. Flash chromatography (ISCO 40 g column,methylene chloride/MeOH 100:0 to 90:10) provided the title compound (673mg, 74%) as a tan solid: ¹H NMR (300 MHz, CD₃OD) δ 8.21 (dd, J=5.4, 1.8Hz, 2H), 7.47 (dd, J=5.6, 1.6 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.06 (dd,J=8.3, 2.4 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 3.87 (s, 3H); ESI MS m/z 235[M+H].

b) 4-(4-Chloro-2-methoxyphenyl)pyridin-2(1H)-one

4-(4-Chloro-2-methoxyphenyl)pyridine 1-oxide (673 mg, 2.86 mmol) andacetic anhydride (10 mL) were heated at reflux for 3 h. The mixture wasconcentrated under reduced pressure, and a 1:1 solution of H₂O/MeOH (20mL) was added. The reaction mixture was heated to reflux for 1 h, cooledto 25° C. and concentrated under reduced pressure. The resulting residuewas dissolved in hot 2-propanol (3 mL), triturated with Et₂O, sonicatedfor 30 min then placed in the freezer. The solid was filtered offproviding the title compound (550 mg, 91%) as a tan solid: ¹H NMR (500MHz, DMSO-d₆) δ 11.54 (s, 1H), 7.35-7.33 (m, 2H), 7.01 (s, 1H), 7.08 (d,J=6.6 Hz, 1H), 6.36 (s, 1H), 6.28 (s, 1H), 3.82 (s, 3H); ESI MS m/z 235[M+H]⁺.

c) tert-Butyl7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

A suspension of 4-(4-chloro-2-methoxyphenyl)pyridin-2(1H)-one (126 mg,0.534 mmol), tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(234 mg, 0.641 mmol), CuI (122 mg, 0.641 mmol), 8-hydroxyquinoline (93mg, 0.64 mmol) and Cs₂CO₃ (191 mg, 0.587 mmol) in DMSO (5 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underAr and heated at 135° C. with stirring overnight. The suspension wascooled, 40:9:1 CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspensionwas stirred at 25° C. for 10 min. The suspension was passed through aplug of silica gel, and the filtrate was washed with brine. The solutionwas dried over Na₂SO₄ and concentrate under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) gave the title compound (123 mg, 44%)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.1 Hz, 1H),7.42-7.35 (m, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.12-7.02 (m, 2H), 6.99 (d,J=1.8 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 6.44 (dd, J=7.2, 1.8 Hz, 1H),4.65 (br s, 2H), 3.88 (s, 3H), 3.90-3.81 (m, 2H), 3.65 (s, 3H),2.87-2.79 (m, 2H), 1.51 (s, 9H).

d)4-(4-Chloro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

TFA (2 mL) was added to a solution of tert-butyl7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(124 mg, 0.238 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) 100:0 to 0:100) yielded 70mg of an off-white solid. 1 M HCl in Et₂O (0.03 ml, 0.03 mmol) was addedto a solution of the off-white solid (10 mg) in CH₂Cl₂ (10 mL) under N₂and the resulting solution was stirred at 25° C. for 30 min. Thesolution was concentrated under reduced pressure to yield the titlecompound (9 mg, 26%) as an off-white powder: mp 290-292° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.17 (br s, 2H), 7.65 (d, J=7.0 Hz, 1H), 7.62 (d, J=1.8Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.26 (d, J=1.8Hz, 1H), 7.14 (dd, J=8.0, 1.8 Hz, 1H), 7.09 (dd, J=8.5, 1.8 Hz, 1H),6.57 (d, J=2.0 Hz, 1H), 6.47 (dd, J=7.0, 2.0 Hz, 1H), 4.37 (br s, 2H),3.87 (s, 3H), 3.70 (s, 3H), 3.57-3.52 (m, 2H), 3.10 (t, J=6.0 Hz, 2H);ESI MS m/z 420 [M+H]⁺.

Example 113 Preparation of4-(4-Chloro-2-methoxyphenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a)4-(4-Chloro-2-methoxyphenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

TFA (2 mL) was added to a solution of tert-butyl7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(124 mg, 0.238 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) yielded 70mg of an off-white solid. Formaldehyde (37% in H₂O, 0.02 mL, 0.2 mmol)was added to a solution of the off-white solid (43 mg) in 1:1MeOH/CH₂Cl₂ (5 mL) and the resulting solution was stirred at 25° C. for45 min. NaBH(OAc)₃ (43 mg, 0.20 mmol) was added to the solution, and theresulting suspension was stirred at 25° C. for 30 min. The suspensionwas concentrated under reduced pressure, and the resulting residue wasdiluted with CH₂Cl₂ and saturated NaHCO₃ solution. The phases wereseparated. The organic phase was dried over Na₂SO₄ and concentratedunder reduced pressure. Purification by semi-preparative HPLC(Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFAand CH₃CN with 0.05% TFA) afforded 13 mg of an off-white solid. 1 M HClin Et₂O (0.03 ml, 0.03 mmol) was added to a solution of the off-whitesolid in CH₂Cl₂ (10 mL) under N₂ and the resulting solution was stirredat 25° C. for 30 min. The solution was concentrated under reducedpressure to yield the title compound (14 mg, 17%) as an off-whitepowder: mp 270-272° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.15 (br s, 1H),7.66 (d, J=7.0 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H),7.44 (d, J=8.5 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.14 (dd, J=8.5, 1.5 Hz,1H), 7.11 (dd, J=8.0, 1.8 Hz, 1H), 6.57 (d, J=2.0 Hz, 1H), 6.47 (dd,J=7.0, 2.0 Hz, 1H), 4.67 (d, J=13.5 Hz, 1H), 4.33 (dd, J=14.3, 6.0 Hz,1H), 3.87 (s, 3H), 3.86-3.79 (m, 1H), 3.71 (s, 3H), 3.55-3.47 (m, 1H),3.24-3.15 (m, 2H), 3.01 (s, 3H); ESI MS m/z 434 [M+H]⁺.

Example 114 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyrimidin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride a) 4-(Pyrimidin-2-ylmethoxy)pyridine 1-oxide

Following the procedure of Example 137 (step a), but substitutingpyrimidin-2ylmethanol (3.0 g, 27 mmol) forimidazo[1,2-a]pyridine-2-ylmethanol, the title compound (0.95 g, 17%)was prepared as an orange solid: ¹H NMR (300 MHz, CD₃OD) δ 8.81 (d,J=5.1 Hz, 2H), 8.23-8.21 (m, 2H), 7.45 (t, J=4.8 Hz, 1H), 7.24-7.21 (m,2H), 5.46 (s, 2H).

b) 4-(Pyrimidin-2-ylmethoxy)pyridin 2(1H)-one

Following the procedure of Example 137 (step b), but substituting4-(pyrimidin-2-ylmethoxy)pyridine 1-oxide (0.95 g, 4.6 mmol) for4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide, the titlecompound (0.55 g, 58%) was prepared as a dark brown solid: ¹H NMR (500MHz, DMSO-d₆) δ 11.09 (br s, 1H), 8.84 (d, J=4.5 Hz, 2H), 7.48 (t, J=5.0Hz, 1H), 7.25-7.23 (m, 1H), 5.92 (dd, J=7.0, 2.5 Hz, 1H), 5.66 (d,J=8.0, 2.5 Hz, 1H), 5.23 (s, 2H).

c) tert-Butyl5-methyl-7-(2-oxo-4-(pyrimidin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

A suspension of 4-(pyrimidin-2-ylmethoxy)pyridin-2(1H)-one (242 mg, 1.19mmol), tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(522 mg, 1.43 mmol), CuI (272 mg, 1.43 mmol), 8-hydroxyquinoline (35 mg,0.24 mmol) and Cs₂CO₃ (426 mg, 1.31 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under Ar andheated at 135° C. with stirring overnight. The suspension was cooled,40:9:1 CH₂Cl₂/MeOH/NH₄OH (50 mL) was added, and the resulting suspensionwas stirred at 25° C. for 1 h. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. The solution wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) yielded the title compound (256 mg,44%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.81 (d, J=4.5 Hz,1H), 7.50 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.31-7.27 (m, 3H),7.01 (br d, J=8.0 Hz, 1H), 6.17 (dd, J=7.5, 2.8 Hz, 1H), 6.00 (d, J=2.8Hz, 1H), 5.32 (s, 2H), 4.64 (br s, 2H), 3.88-3.79 (m, 2H), 3.62 (s, 3H),2.84-2.78 (m, 2H), 1.50 (s, 9H).

d)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyrimidin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride

TFA (2 mL) was added to a solution of tert-butyl5-methyl-7-(2-oxo-4-(pyrimidin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(256 mg, 0.525 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(4:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) yielded 35mg of a yellow foam. 1 M HCl in Et₂O (0.08 ml, 0.08 mmol) was added to asolution of the yellow foam (16 mg) in CH₂Cl₂ (10 mL) under N₂, and theresulting solution was stirred at 25° C. for 30 min. The solution wasconcentrated under reduced pressure to yield the title compound (16 mg,14%) as an off-white powder: mp 234-236° C.; ¹H NMR (500 MHz, DMSO-d₆) δ9.10 (br s, 2H), 8.88 (d, J=5.0 Hz, 2H), 7.58-7.52 (m, 4H), 6.99 (dd,J=8.0, 1.8 Hz, 1H), 6.14 (dd, J=7.5, 2.5 Hz, 1H), 5.86 (d, J=2.5 Hz,1H), 5.33 (s, 2H), 4.36 (br s, 2H), 3.68 (s, 3H), 3.57-3.52 (m, 2H),3.11-3.05 (m, 2H); ESI MS m/z 388 [M+H]⁺.

Example 115 Preparation of4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

A suspension of 4-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2(1H)-one(270 mg, 1.12 mmol), tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(493 mg, 1.35 mmol), CuI (257 mg, 1.35 mmol), 8-hydroxyquinoline (98 mg,0.67 mmol) and Cs₂CO₃ (401 mg, 1.23 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under Ar andheated at 135° C. with stirring for 4.5 h. The suspension was cooled,40:9:1 CH₂Cl₂/MeOH/NH₄OH (50 mL) was added, and the resulting suspensionwas stirred at 25° C. for 30 min. The suspension was passed through aplug of silica gel, and the filtrate was washed with brine. The solutionwas dried over Na₂SO₄ and concentrate under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) yielded the title compound (167 mg,28%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.34-8.25 (m, 1H),7.79-7.61 (m, 3H), 7.58-7.50 (m, 1H), 7.40-7.25 (m, 3H), 7.07-6.69 (m,1H), 6.17-6.10 (m, 1H), 6.09-6.02 (m, 1H), 5.11 (s, 2H), 4.65 (br s,2H), 3.92-3.80 (m, 2H), 3.65 (s, 3H), 2.89-2.80 (m, 2H), 1.52 (s, 9H);ESI MS m/z 526 [M+H]⁺.

b)4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

TFA (2 mL) was added to a solution of tert-butyl7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(167 mg, 0.317 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(4:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) yielded 51mg of a yellow solid. Purification by semi-preparative HPLC (PhenomenexLuna C18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CNwith 0.05% TFA) afforded 7 mg of a white solid. 1 M HCl in Et₂O (0.03ml, 0.03 mmol) was added to a solution of the white solid (7 mg) inCH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirred at 25°C. for 30 min. The solution was concentrated under reduced pressure toyield the title compound (8 mg, 5%) as a white powder: ¹H NMR (500 MHz,DMSO-d₆) δ 9.28 (br s, 2H), 9.06 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H),8.05-7.94 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.50(d, J=1.5 Hz, 1H), 6.99 (dd, J=8.0, 1.5 Hz, 1H), 6.13 (dd, J=7.5, 2.5Hz, 1H), 6.09 (d, J=2.5 Hz, 1H), 5.33 (s, 2H), 4.35 (br s, 2H), 3.69 (s,3H), 3.56-3.50 (m, 2H), 3.12-3.05 (m, 2H); ESI MS m/z 426 [M+H]⁺.

Example 116 Preparation of4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

A suspension of 4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one(231 mg, 0.960 mmol), tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(421 mg, 1.15 mmol), CuI (219 mg, 1.15 mmol), 8-hydroxyquinoline (84 mg,0.576 mmol) and Cs₂CO₃ (345 mg, 1.06 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under Ar andheated at 135° C. with stirring overnight. The suspension was cooled,40:9:1 CH₂Cl₂/MeOH/NH₄OH (50 mL) was added, and the resulting suspensionwas stirred at 25° C. for 30 min. The suspension was passed through aplug of silica gel, and the filtrate was washed with brine and 10% CuSO₄solution. The solution was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(4:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) gave thetitle compound (132 mg, 26%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃)δ 8.12 (d, J=6.9 Hz, 1H), 7.70 (br s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.50(d, J=8.4 Hz, 1H), 7.33-7.18 (m, 3H), 7.02 (d, J=7.5 Hz, 1H), 6.82 (dd,J=6.9, 6.9 Hz, 1H), 6.17 (d, J=2.1 Hz, 1H), 6.08 (dd, J=7.5, 2.1 Hz,1H), 5.25 (s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.84-2.79 (m, 2H),1.72-1.60 (m, 2H), 1.50 (s, 9H).

b)4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

TFA (1 mL) was added to a solution of tert-butyl7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(132 mg, 0.251 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theaqueous phase was extracted with EtOAc. The combined organic phases weredried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) yielded 42 mg of an off-white solid.1 M HCl in Et₂O (0.07 ml, 0.07 mmol) was added to a solution of theoff-white solid (15 mg) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 30 min. The solution was concentratedunder reduced pressure to yield the title compound (15 mg, 34%) as awhite powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (br s, 2H), 8.84 (s, 1H),8.37 (s, 1H), 7.89-7.70 (m, 2H), 7.64-7.53 (m, 2H), 7.50 (s, 1H),7.37-7.29 (m, 1H), 7.03-6.97 (m, 1H), 6.20-6.09 (m, 2H), 5.41 (s, 2H),4.35 (br s, 2H), 3.69 (s, 3H), 3.58-3.50 (m, 2H), 3.13-3.07 (m, 2H); ESIMS m/z 426 [M+H]⁺.

Example 117 Preparation of1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride a)1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-onedihydrochloride

TFA (1 mL) was added to a solution of tert-butyl7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(132 mg, 0.251 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution andCH₂Cl₂ were added to the solution, and the phases were separated. Theaqueous phase was extracted with EtOAc. The combined organic phases weredried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) yielded 42 mg of an off-white solid.Formaldehyde (37% in H₂O, 0.01 mL, 0.12 mmol) was added to a solution ofthe off-white solid (27 mg) in 1:1 MeOH/CH₂Cl₂ (5 mL), and the resultingsolution was stirred at 25° C. for 45 min. NaBH(OAc)₃ (27 mg, 0.13 mmol)was added to the solution, and the resulting suspension was stirred at25° C. for 30 min. The suspension was concentrated under reducedpressure, and the residue was diluted with CH₂Cl₂ and saturated NaHCO₃solution. The phases were separated. The organic phase was dried overNa₂SO₄ and concentrated under reduced pressure to afford 25 mg of aviscous oil. 1 M HCl in Et₂O (0.11 ml, 0.11 mmol) was added to asolution of the off-white solid in CH₂Cl₂ (10 mL) under N₂, and theresulting solution was stirred at 25° C. for 30 min. The solution wasconcentrated under reduced pressure to yield the title compound (25 mg,30%) as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) 10.79 (br s, 1H),8.87 (d, J=6.5 Hz, 1H), 8.41 (s, 1H), 7.90-7.78 (m, 2H), 7.61 (d, J=7.5Hz, 1H), 7.53-7.49 (m, 2H), 7.42-7.35 (m, 1H), 7.00 (dd, J=8.5, 1.5 Hz,1H), 6.15 (d, J=2.5 Hz, 1H), 6.12 (dd, J=7.5, 2.5 Hz, 1H), 5.43 (s, 2H),4.62 (d, J=14.0 Hz, 1H), 4.29 (dd, J=14.0, 7.5 Hz, 1H), 3.80-3.75 (m,1H), 3.69 (s, 3H), 3.55-3.46 (m, 1H), 3.23-3.16 (m, 2H), 2.97 (s, 3H);ESI MS m/z 440 [M+H]⁺.

Example 118 Preparation of1-(2-Acetyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(benzyloxy)pyridin-2(1H)-one

AcCl (0.023 mL, 0.32 mmol) was added to a solution of4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride (100 mg, 0.216 mmol), DMAP (5 mg, 0.04 mmol) and Et₃N(0.09 mL, 0.6 mmol) in CH₂Cl₂ (20 mL) under N₂, and the resultingsolution was stirred at 25° C. for 4 h. H₂O was added to the solution,and the phases were separated. The organic phase was washed withsaturated NH₄Cl solution, dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) affordedthe title compound (61 mg, 66%) as a mixture of rotomers as a whitepowder: mp 80-82° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.56 (d, J=7.5 Hz,1H), 7.52-7.35 (m, 7H), 6.94 (dd, J=8.0, 1.5 Hz, 1H), 6.12-6.08 (m, 1H),5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.77-4.72 (m, 2H), 3.82-3.72 (m,2H), 3.69-3.65 (m, 3H), 3.82-2.78 (m, 1.3H), 2.71-2.68 (m, 0.7H), 2.16(s, 3H); ESI MS m/z 428 [M+H]⁺.

Example 119 Preparation of1-(2-Acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

AcCl (0.03 mL, 0.4 mmol) was added to a solution of1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one(125 mg, 0.294 mmol), DMAP (7 mg, 0.06 mmol) and Et₃N (0.08 mL, 0.6mmol) in CH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirredat 25° C. for 17 h. H₂O was added to the solution, and the phases wereseparated. The organic phase was washed with saturated NH₄Cl solution,dried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded the title compound (116 mg,84%) as a mixture of rotomers as a white powder: mp 232-236° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.35 (d,J=8.3 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.28 (d, J=1.5Hz, 1H), 7.08-7.03 (m, 2H), 4.70 (s, 0.8H), 4.68 (s, 1.2H), 3.88 (t,J=5.5 Hz, 0.8H), 3.83 (t, J=5.5 Hz, 1.2H), 3.67 (s, 3H), 2.97-2.91 (m,1.2H), 2.86-2.81 (m, 0.8H), 2.15 (s, 1.8H), 2.13 (s, 1.2H); ESI MS m/z467 [M+H]⁺.

Example 120 Preparation of1-(2-Ethyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

2-Picoline borane (63 mg, 0.59 mmol) was added to a suspension of1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride (98 mg, 0.20 mmol) and acetylaldhyde (0.03 mL, 1 mmol)in 9:1 CH₂Cl₂/AcOH (10 mL) under N₂, and the resulting solution wasstirred under N₂ for 4 h. Acetylaldhyde (0.03 mL, 1 mmol) was added tothe solution under N₂ and the resulting solution was stirred at 25° C.for 15 min. The solution was neutralized with saturated NaHCO₃ solution,and the phases were separated. The organic phase was dried over Na₂SO₄and concentrated under reduced pressure. Flash chromatography (silicagel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded 67 mg of a yellow powder. 2 N HCl in Et₂O (0.15 mL, 0.330 mmol)was added to a solution of the yellow powder in 1:1 MeOH/CH₂Cl₂ (10 mL)under N₂, and the resulting solution was stirred at 25° C. for 15 min.Et₂O was added to the solution, and the resulting suspension wasfiltered under N₂ to afford the title compound (78 mg, 75%) as a yellowpowder: mp 300-302° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (br s, 1H),9.15 (s, 1H), 8.42-8.35 (m, 2H), 7.85 (d, J=7.0 Hz, 1H), 7.65 (d, J=1.5Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.13 (dd,J=8.5, 1.5 Hz, 1H), 7.08 (dd, J=7.5, 2.0 Hz, 1H), 4.70 (d, J=12.5 Hz,1H), 4.32 (dd, J=14.5, 8.0 Hz, 1H), 3.91-3.83 (m, 1H), 3.72 (s, 3H),3.52-3.43 (m, 1H), 3.41-3.30 (m, 2H), 3.24-3.16 (m, 2H), 1.38 (t, J=7.3Hz, 3H); ESI MS m/z 453 [M+H]⁺.

Example 121 Preparation of1-(2-Isopropyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

2-Picoline borane (87 mg, 0.81 mmol) was added to a suspension of1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride (134 mg, 0.27 mmol) and acetone (0.10 mL, 1.4 mmol) in9:1 CH₂Cl₂/AcOH (10 mL) under N₂, and the resulting solution was stirredfor 24 h. Acetone (1 mL) was added to the solution and the resultingsolution was stirred at 25° C. for 24 h. Acetone (1 mL) and 2-picolineborane (87 mg, 0.81 mmol) were added to the solution, and the resultingsolution was stirred at reflux for 24 h. The solution was cooled, H₂Owas added, and the reaction mixture was neutralized with saturatedNaHCO₃ solution. The phases were separated, and the organic phase wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 88 mg of a yellow powder. 2N HCl in Et₂O (0.15 mL, 0.330 mmol) was added to a solution of theyellow powder in 1:1 MeOH/CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 30 min. Et₂O was added to thesolution, and the resulting solid was collected by filtration under N₂.The solid was washed with Et₂O to afford the title compound (25 mg, 17%)as a yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br s, 1H), 9.15(d, J=2.0 Hz, 1H), 8.42-8.35 (m, 2H), 7.85 (d, J=7.5 Hz, 1H), 7.66 (d,J=1.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.14 (dd,J=8.5, 1.5 Hz, 1H), 7.08 (dd, J=7.5, 2.0 Hz, 1H), 4.58 (d, J=13.0 Hz,1H), 4.48-4.40 (m, 1H), 3.90-3.82 (m, 1H), 3.78-3.70 (m, 4H), 3.51-3.42(m, 1H), 3.38-3.15 (m, 2H), 1.45-1.36 (m, 6H); ESI MS m/z 467 [M+H]⁺.

Example 122 Preparation of4-(4-Methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(4-Methoxyphenyl)pyridin-2(1H)-one

A suspension of 4-bromo-2-methoxypyridine (1.22 g, 6.49 mmol),4-methoxyphenyl boronic acid (1.97 g, 13.0 mmol), PdCl₂(dppf) (530 mg,0.649 mmol) and K₂CO₃ (1.79 g, 13.0 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under Ar andstirred at 95° C. for 2 h. The suspension was cooled, H₂O was added, andthe suspension was filtered to afford a light colored solid. Flashchromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100)afforded 1.10 g of a white powder. The white powder was diluted withconcentrated HCl solution (50 mL) and stirred at reflux for 12 h. Thereaction was cooled and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded the title compound (313 mg,24%) as a white powder: ¹H NMR (300 MHz, DMSO-d₆) δ 11.47 (s, 1H), 7.65(d, J=8.7 Hz, 2H), 7.38 (d, J=6.8 Hz, 1H), 7.01 (d, J=8.7 Hz, 2H), 6.51(br s, 1H), 6.47 (d, J=6.8 Hz, 1H), 3.79 (s, 3H).

b) tert-Butyl7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

pressure to yield the title compound (47 mg, 55%) as a yellow powder: mp306-308° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (br s, 2H), 7.76 (d, J=9.0Hz, 2H), 7.70 (d, J=7.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.11-7.05 (m, 3H),6.73 (d, J=2.0 Hz, 1H), 6.68 (dd, J=7.0, 2.0 Hz, 1H), 4.51-4.45 (m, 2H),3.83 (s, 3H), 3.70 (s, 3H), 3.48-3.42 (m, 2H), 2.99 (t, J=6.0 Hz, 2H);ESI MS m/z 386 [M+H]⁺.

Example 123 Preparation of1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(methylthio)phenyl)pyridin-2(1H)-onehydrochloride a) 4-(4-(Methylthio)phenyl)pyridin-2(1H)-one

A suspension of 4-bromo-2-methoxypyridine (1.225 g, 6.511 mmol),4-methylthiophenyl boronic acid (2.188 g, 13.02 mmol), PdCl₂(dppf) (531mg, 0.651 mmol) and K₂CO₃ (1.797 g, 13.02 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 25 min. The suspension was put underN₂ and stirred at 95° C. for 16 h. The suspension was cooled, H₂O wasadded, and the suspension was filtered to afford a light colored solid.Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to0:100) afforded 1.10 g of a white powder. The white powder was dilutedwith concentrated HCl solution (50 mL) and stirred at reflux for 24 h.The reaction was cooled and concentrated under reduced pressure. Theresidue was neutralized with saturated NaHCO₃ solution, and the solidwas collected by filtration. The solid was washed with H₂O to afford thetitle compound (1.103 g, 71%) as a tan solid: ¹H NMR (300 MHz, DMSO-d₆)δ 7.65 (d, J=8.4 Hz, 2H), 7.43 (d, J=6.9 Hz, 1H), 7.34 (d, J=8.4 Hz,2H), 6.57 (d, J=1.7 Hz, 1H), 6.50 (dd, J=6.9, 1.7 Hz, 1H), 3.34 (s, 3H).

A mixture of 4-(1,3-dioxolan-2-yl)-2-methylbutan-2-amine (3.28 g, 20.4mmol), 3-bromophenylhydrazine hydrochloride (4.34 g, 19.4 mmol) andZnCl₂ (2.90 g, 21.3 mmol) was stirred at 180° C. for 2.5 h. The mixturewas cooled to 120° C., MeOH was added, and the resulting suspension wasconcentrated on silica gel. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded4.20 g of a red amorphous solid. Glyoxylic acid (1.87 g, 20.4 mmol) wasadded to a suspension of the red amorphous solid in 4:2:1H₂O/MeOH/(concentrated HCl solution) (70 mL), and the resulting solutionwas stirred at 25° C. for 30 min. The solution was adjusted to pH 3.5with 6 N NaOH in H₂O, and the resulting solution was stirred at 25° C.overnight. The solution was adjusted to pH 5 with saturated NaHCO₃solution and the suspension was filtered. The solid was diluted with 2 NHCl in H₂O, and the resulting suspension was stirred at reflux for 2.5h. The solution was concentrated under reduced pressure and neutralizedwith saturated NaHCO₃ solution. The resulting suspension was filtered,and the solid was dissolved in CH₂Cl₂. The resulting solution was driedover Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 577 mg of a white solid.Boc₂O (2.71 g, 12.4 mmol) was added to a suspension of the white solidand K₂CO₃ (571 mg, 4.14 mmol) in 1:1 H₂O/i-PrOH (40 mL), and theresulting suspension was stirred at 25 C for 5.5 h. The suspension wasconcentrated under reduced pressure, and the residue was diluted withwater. The solid was collected by filtration, and flash chromatography(silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded thetitle compound (200 mg, 3%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.83 (br s, 1H), 7.47 (br s, 1H), 7.31 (br d, J=8.7 Hz, 1H), 7.20 (br d,J=8.7 Hz, 1H), 4.62 (br s, 2H), 2.77 (br s, 2H), 1.53 (s, 6H), 1.48 (s,9H).

c) tert-Butyl7-bromo-3,3,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylateb)1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(methylthio)phenyl)pyridine-2(1H)-onehydrochloride

A suspension of 4-(4-(methylthio)phenyl)pyridine-2(1H)-one (134 mg,0.615 mmol), tert-butyl7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(247 mg, 0.676 mmol), CuI (140 mg, 0.738 mmol), 8-hydroxyquinoline (18mg, 0.12 mmol) and Cs₂CO₃ (220 mg, 0.676 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. overnight. The suspension was cooled,9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 179 mg of a yellow powder.2 N HCl in Et₂O (300 mL) was added to a solution of the yellow powder in1:1 CH₂Cl₂/MeOH (8 mL) under N₂, and the resulting suspension wasstirred at 25° C. for 17 h. The suspension was filtered and the solidwas washed with CH₂Cl₂ and 99:1 CH₂Cl₂/MeOH to afford the title compound(41 mg, 15%) as an off-white solid: mp 306-310° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.27 (br s, 2H), 7.77-7.71 (m, 3H), 7.61-7.58 (m, 2H), 7.39(d, J=8.5 Hz, 2H), 7.09 (dd, J=8.5, 2.0 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H),6.69 (dd, J=7.5, 2.0 Hz, 1H), 4.36 (br s, 2H), 3.70 (s, 3H), 3.56-3.51(m, 2H), 3.10 (t, J=5.5 Hz, 2H), 2.54 (s, 3H); ESI MS m/z 402 [M+H]⁺.

Example 124 Preparation of1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(methylthio)phenyl)pyridine-2(1H)-onehydrochloride a) tert-Butyl9-methyl-7-(4-(4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

A suspension of 4-(4-(methylthio)phenyl)pyridine-2(1H)-one (110 mg,0.505 mmol), tert-butyl7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(203 mg, 0.555 mmol), CuI (115 mg, 0.606 mmol), 8-hydroxyquinoline (15mg, 0.10 mmol) and Cs₂CO₃ (181 mg, 0.555 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. overnight. The suspension was cooled,9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded the title compound (97 mg,38%) as an off-white powder: ¹H NMR (500 MHz, CDCl₃) δ 7.61-7.54 (m,3H), 7.48 (d, J=7.5 Hz, 1H), 7.38-7.32 (m, 3H), 7.08 (dd, J=8.5, 2.0 Hz,1H), 6.89 (d, J=2.0 Hz, 1H), 6.50 (dd, J=7.5, 2.0 Hz, 1H), 4.70-4.61 (m,2H), 3.81-3.73 (m, 2H), 3.65 (s, 3H), 2.84-2.78 (m, 2H), 2.54 (s, 3H),1.52 (s, 9H).

b)1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(methylthio)phenyl)pyridine-2(1H)-onehydrochloride

TFA (1 ml) was added to a solution of tert-butyl9-methyl-7-(4-(4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(97 mg, 0.19 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred for 1.5 h at 25° C. Saturated NaHCO₃ solution wasadded to the reaction mixture, and the resulting suspension wasfiltered. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded35 mg of a yellow powder. 2 N HCl in Et₂O (0.09 mL, 0.09 mmol) was addedto a solution of the yellow solid in CH₂Cl₂ (10 mL) under N₂, and theresulting solution was stirred at 25° C. for 15 min. Et₂O was added tothe solution, and the resulting suspension was filtered under N₂. Thesolid was washed with Et₂O to afford the title compound (37 mg, 17%) asa yellow powder: mp 300-304° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (br s,2H), 7.75 (d, J=8.5 Hz, 2H), 7.73 (d, J=7.3 Hz, 1H), 7.62-7.58 (m, 2H),7.38 (d, J=8.5 Hz, 2H), 7.10 (dd, J=8.5, 2.0 Hz, 1H), 6.78 (d, J=2.0 Hz,1H), 6.69 (dd, J=7.3, 2.0 Hz, 1H), 4.49 (br s, 2H), 3.70 (s, 3H),3.60-3.32 (m, 2H), 2.99 (t, J=5.5 Hz, 2H), 2.54 (s, 3H); ESI MS m/z 402[M+H]⁺.

Example 125 Preparation of4-(Benzyloxy)-1-(3,39-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-onehydrochloride a) 4-(1,3-Dioxolan-2-yl)-2-methylbutan-2-amine

Beilstein Registry Number 9387059

This compound was prepared in accordance with the procedure ofHinderaker, et al., Protien Sci. 2003, 12, 1188-1194.

b) tert-Butyl7-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

NaH (60% dispersion in oil, 42 mg, 1.1 mmol) was added to a solution oftert-butyl7-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(200 mg, 0.528 mmol) in DMF (10 mL) under N₂, and the resultingsuspension was stirred at 25° C. for 30 min. MeI (0.05 mL, 0.8 mmol) wasadded to the suspension, and the resulting suspension was stirred at 25°C. for 1 h. H₂O was added, and the resulting solid was collected byfilteration. Flash chromatography (silica gel, hexanes/(1:1EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (145 mg,70%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.43 (d, J=1.5 Hz, 1H),7.30 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.3, 1.5 Hz, 1H), 4.62 (s, 2H), 3.61(s, 3H), 2.77 (s, 2H), 1.52 (s, 6H), 1.49 (s, 9H).

d)4-(Benzyloxy)-1-(3,3,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-onehydrochloride

A suspension of 4-(benzyloxy)pyridine-2(1H)-one (67 mg, 0.34 mmol),tert-butyl7-bromo-3,3,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(145 mg, 0.369 mmol), CuI (76 mg, 0.40 mmol), 8-hydroxyquinoline (10 mg,0.07 mmol) and Cs₂CO₃ (120 mg, 0.369 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under Ar andstirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 28 mg of a white solid. TFA(1 ml) was added to a solution of the white solid in CH₂Cl₂ (10 mL)under N₂, and the resulting solution was stirred for 1 h at 25° C.Saturated NaHCO₃ solution was added to the solution, and the phases wereseparated. The aqueous phase was extracted with CH₂Cl₂, and the combinedorganic extracts were dried over Na₂SO₄. The resulting solution wasconcentrated under reduced pressure. Flash chromatography (silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded 14 mg of a white powder. 2 N HCl in Et₂O (0.01 mL, 0.02 mmol)was added to a solution of the white solid in CH₂Cl₂ (10 mL) under N₂,and the resulting solution was stirred at 25° C. for 30 min. Thesolution was concentrated under reduced pressure to afford the titlecompound (5.2 mg, 3%) as a white powder: mp 184-186° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.34 (br s, 2H), 7.57 (d, J=7.5 Hz, 1H), 7.53-7.50 (m,2H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, 1H), 6.99 (dd, J=8.0, 2.0 Hz, 1H),6.11 (dd, J=8.0, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.50(br s, 2H), 3.70 (s, 3H), 2.89 (s, 2H), 1.42 (s, 6H); ESI MS m/z 414[M+H]⁺.

Example 126 Preparation of4-(4-Methoxy-2-methylphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(4-Methoxy-2-methylphenyl)pyridin-2(1H)-one

A suspension of 4-bromo-2-methoxypyridine (341 mg, 1.82 mmol),4-methyloxy-2-methylphenyl boronic acid (452 mg, 2.72 mmol),Pd(PPh₃)₂Cl₂ (133 mg, 0.182 mmol) and K₂CO₃ (503 mg, 3.64 mmol) in DMSO(10 mL) was degassed under reduced pressure for 1 h. The suspension wasput under Ar and stirred at 90° C. for 2 h. The suspension was cooled,H₂O was added, and the suspension was filtered to afford a light coloredsolid. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes),100:0 to 0:100) afforded 235 mg of a white powder. The white powder wasdiluted with concentrated HCl solution (20 mL) and stirred at reflux for24 h. The reaction was cooled and concentrated under reduced pressure.The residue was neutralized with saturated NaHCO₃ solution, and thesolid was collected by filtration. Flash chromatography (silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded the title compound (62 mg, 16%) as a white powder: ¹H NMR (300MHz, DMSO-d₆) δ 11.54 (br s, 1H), 7.35 (d, J=6.9 Hz, 1H), 7.13 (d, J=8.4Hz, 1H), 6.87-6.76 (m, 2H), 6.15-6.09 (m, 2H), 3.75 (s, 3H), 1.97 (s,3H).

b)4-(4-Methoxy-2-methylphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(4-methoxy-2-methylphenyl)pyridin-2(1H)-one (62 mg,0.29 mmol), tert-butyl7-bromo-3,3,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(126 mg, 0.344 mmol), CuI (66 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg,0.06 mmol) and Cs₂CO₃ (103 mg, 0.316 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under Ar andstirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 1 h. The suspension was passed through a plug ofsilica gel, and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 52 mg of a yellow amorphoussolid. TFA (1 ml) was added to a solution of the yellow amorphous solidin CH₂Cl₂ (10 mL) under N₂ and the resulting solution was stirred for 1h at 25° C. Saturated NaHCO₃ solution was added to the solution, and thephases were separated. The aqueous phase was extracted with CH₂Cl₂, andthe combined organic extracts were dried over Na₂SO₄. The resultingsolution was concentrated under reduced pressure. Flash chromatography(silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to0:100) afforded 19 mg of a viscous oil. 1 N HCl in Et₂O (0.05 mL, 0.05mmol) was added to a solution of the viscous oil in CH₂Cl₂ (10 mL) underN₂, and the resulting solution was stirred at 25° C. for 30 min. Thesolution was concentrated under reduced pressure to afford the titlecompound (16 mg, 13%) as a white powder: mp 308-310° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.44 (br s, 2H), 7.67 (d, J=7.0 Hz, 1H), 7.63 (d, J=1.5Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.11 (dd,J=8.5, 1.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.88 (dd, J=8.5, 2.5 Hz,1H), 6.37 (s, 1H), 6.34 (dd, J=7.5, 1.5 Hz, 1H), 4.89 (br s, 2H), 3.79(s, 3H), 3.70 (s, 3H), 3.49-3.43 (m, 2H), 2.99 (t, J=6.0 Hz, 2H), 2.36(s, 3H); ESI MS m/z 400 [M+H]⁺.

Example 127 Preparation of4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-onehydrochloride a)4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one

1-(2-Chloroethyl)pyrrolidine hydrochloride (50 mg, 0.29 mmol) was addedto a solution of4-(benzyloxy)-1-(9-methyl-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one(0.10 g, 0.27 mmol) and diisoproylethyl amine (0.14 mL) in EtOH (4 mL),and the resulting solution was heated at 65° C. for 2 h. The reactionmixture was concentrated to dryness under reduced pressure. Purificationby flash column chromatography (40 g ISCO column, CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 hold 5 column volumes increased to 0:100 over20 column volumes) followed by preparative TLC (Analtech, 20×20 cm, 1000microns, uV 254, 80:18:2 CH₂Cl₂/MeOH/NH₄OH) followed by preparative HPLC(Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H₂O with 0.05% TFAand CH₃CN with 0.05% TFA) and filtration through SCX-2 column gave thetitle compound (10 mg, 7%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ7.54 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.46-7.33 (m, 6H), 6.96(dd, J=8.0, 1.5 Hz, 1H), 6.26 (dd, J=7.5, 2.5, Hz, 1H), 6.11 (d, J=3.0Hz, 1H), 5.16 (s, 2H), 3.82 (s, 2H), 3.64 (s, 3H), 3.01-2.99 (m, 2H),2.94-2.85 (m, 10H), 1.91-1.90 (m, 4H); HPLC (Method A) 95.1% (AUC),t_(R)=13.8 min.

b)4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-onehydrochloride

2 N HCl in Et₂O (20 μL, 0.04 mmol) was added to a solution of4-(benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one(10 mg, 0.020 mmol) in CH₂Cl₂ (3 mL) and the reaction was stirred atambient temperature for 1 h under N₂. The reaction was concentrated todryness under reduced pressure to provide the title compound (10 mg,quantitative) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 7.62-7.57 (m,2H), 7.47-7.34 (m, 6H), 7.03 (dd, J=8.5, 1.5 Hz, 1H), 6.29 (dd, J=7.5,2.5 Hz, 1H), 6.12 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.55-4.43 (m, 2H),3.72 (s, 3H), 3.38-3.14 (m, 12H), 2.14 (m, 4H); ESI MS m/z 483 [M+H]⁺;HPLC (Method A) 92.8% (AUC), t_(R)=13.6 min.

Example 128 Preparation of4-(4-Chloro-2-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a)tert-Butyl-7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(0.19 g, 0.81 mmol), 4-(4-chloro-2-methoxyphenyl)pyridin-2(1H)-one (0.30g, 0.81 mmol), Cs₂CO₃ (0.29 g, 0.89 mmol) were diluted with DMSO (3.3mL), and argon was bubbled through the suspension for 10 min.8-Hydroxyquinoline (59 mg, 0.41 mmol) and copper iodide (0.18 g, 0.97mmol) were added, and the resulting suspension was placed under vacuumfor 15 min. The system was flushed with argon, and the degassing/argonflushing process was repeated a total of three times. The reactionmixture was heated at 130° C. for 18 h and stirred under argon. Thesuspension was cooled. A solution of 20% NH₄OH in MeOH (40 mL) wasadded, and the resulting mixture was stirred for 1 h. The mixture wasdiluted with CH₂Cl₂ and filtered through celite. The filtrate was washedwith brine (2×50 mL), dried over Na₂SO₄, and concentrated under reducedpressure. Flash chromatography (40 g ISCO (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 3 column volumnes then increase to 50:50over 10 column volumnes and hold for 10 column volumes) gave the titlecompound (0.23 g, 54%) as an olive-green film: ¹H NMR (500 MHz, DMSO-d₆)δ 7.65 (d, J=7.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.0 Hz,1H), 7.44 (d, J=8.0 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.13 (dd, J=8.0,1.5 Hz, 1H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 6.55 (d, J=2.0 Hz, 1H), 6.54(dd, J=7.0, 1.5 Hz, 1H), 4.64 (s, 2H), 3.87 (s, 3H), 3.68-3.66 (m, 5H),2.74-2.72 (m, 2H), 1.46 (s, 9H).

b)4-(4-Chloro-2-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Trifluoroacetic acid (1.0 mL) was added to a solution oftert-butyl-7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(0.23 g, 0.44 mmol) in CH₂Cl₂ (2 mL) under argon and stirred for 1 h.The mixture was concentrated under reduced pressure, and the residue waspartitioned between CH₂Cl₂ and saturated NaHCO₃ solution. The organicphase was removed, and the aqueous phase was extracted with CH₂Cl₂(10×25 mL). The combined organic extracts were washed with brine (25mL), dried over Na₂SO₄, and concentrated under reduced pressure. Flashcolumn chromatography (12 g ISCO CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH),100:0 for 2 column volumes to 0:100 over 20 column volumes and hold for10 column volumes) provided the free base of the title compound. Thefree base was converted to the HCl salt using 2 N HCl in Et₂O as ofExample 129 (step b), providing the title compound (0.13 g, 33%) as ayellow solid: mp 294-300° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (br s,2H), 7.65 (d, J=7.0 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.59 (d, J=8.0 Hz,1H), 7.44 (d, J=8.5 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.5,2.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.47(dd, J=7.0, 1.5 Hz, 1H), 4.49-4.47 (m, 2H), 3.87 (m, 3H), 3.69 (s, 3H),3.47-3.43 (m, 2H), 3.00-2.97 (m, 2H); ESI MS m/z 420 [M+H]⁺; HPLC(Method A) 96.7% (AUC), t_(R)=15.5 min.

Example 129 Preparation of4-(4-Chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride a)4-(4-Chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

4-(4-Chloro-2-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(83 mg, 0.20 mmol) and 37% aqueous formaldehyde (24 μL, 0.30 mmol) weredissolved in 1:1 MeOH/CH₂Cl₂ (1.4 mL) and stirred at room temperaturefor 45 min. Sodium triacetoxyborohydride (84 mg, 0.40 mmol) was added,and the reaction was stirred at ambient temperature for 30 min. Thereaction mixture was neutralized with saturated NaHCO₃ solution andextracted with CH₂Cl₂ (3×25 mL). The combined organics were washed withbrine (25 mL), dried over Na₂SO₄, filtered and concentrated to drynessunder reduced pressure. Purification by flash column chromatography (12g ISCO (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 95:5 to 10:90over 20 column volumes, hold for 10 column volumes) provided the titlecompound (77 mg, 89%) as a yellow film: ¹H NMR (500 MHz, CDCl₃) δ 7.55(d, J=8.0 Hz, 1H), 7.41 (d, J=7.0 Hz, 1H), 7.35-7.34 (m, 1H), 7.31 (d,J=8.0 Hz, 1H), 7.07-7.03 (m, 2H), 7.00-6.99 (m, 1H), 6.81-6.80 (m, 1H),6.43-6.42 (m, 1H), 3.87 (s, 3H), 3.66-3.65 (m, 2H), 3.48 (s, 3H),2.87-2.86 (m, 2H), 2.81-2.80 (m, 2H), 2.58 (s, 3H).

b)4-(4-Chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

2 N HCl in Et₂O (0.17 mL, 0.34 mmol) was added to a solution of4-(4-chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(74 mg, 0.17 mmol) in CH₂Cl₂ (2 mL) and the reaction was stirred atambient temperature for 1.5 h under N₂. The solids were collected byfiltration, washed with Et₂O and dried under reduced pressure to yieldthe title compound (54 mg, 68%) as a yellow powder: mp 272-280° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 10.82 (br s, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.62(d, J=1.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.26(d, J=1.5 Hz, 1H), 7.14-7.09 (m, 2H), 6.56 (d, J=1.5 Hz, 1H), 6.47 (dd,J=7.0, 1.5 Hz, 1H), 4.79-4.76 (m, 1H), 4.53-4.42 (m, 1H), 3.87 (s, 3H),3.72-3.68 (m, 4H), 3.42-3.40 (m, 1H), 3.08-3.06 (m, 2H), 3.00 (s, 3H);ESI MS m/z 434 [M+H]⁺; HPLC (Method A) 96.5% (AUC), t_(R)=15.3 min.

Example 130 Preparation of(S)-4-(Benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-onehydrochloride a) (S)-tert-Butyl2-((7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)methyl)pyrrolidine-1-carboxylate

A solution of (S)-tert-butyl-2-(bromomethyl)pyrrolidine-1-carboxylate(0.45 g, 1.7 mmol) in DMSO (1.5 mL) was added to a solution of4-(benzyloxy)-1-(9-methyl-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one(0.33 g, 0.85 mmol), and Cs₂CO₃ (1.10 g, 3.4 mmol) in DMSO (2.8 mL), andthe resulting solution was heated at 60° C. for 18 h. The reactionmixture was diluted with H₂O and extracted with CH₂Cl₂ (3×25 mL). Thecombined organic extracts were washed with brine (2×25 mL), dried overNa₂SO₄ and concentrated to dryness under reduced pressure. Purificationby flash column chromatography (40 g ISCO column, CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 hold 5 column volumes, increased to 0:100:0over 20 column volumes) provided a clear film. The film was diluted withEtOAc and washed with brine (4×10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide the title compound (19mg, 3%) as a clear film: ESI MS m/z 569 [M+H]⁺.

b)(S)-4-(Benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution of (S)-tert-butyl2-((7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)methyl)pyrrolidine-1-carboxylate(19 mg, 0.033 mmol) in 2:1 CDCl₃/MeOH (1.5 mL) under argon and stirredfor 30 min. The mixture was concentrated to dryness under reducedpressure. Flash column chromatography (4 g ISCO CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 95:5 for 20 column volumes to 0:100 over 40 columnvolumes and hold for 100 column volumnes) yielded the title compound (10mg, 65%) as a clear film: ESI MS m/z 469 [M+H]⁺

c)(S)-4-(Benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-onehydrochloride

2 N HCl in Et₂O (0.12 μL, 0.024 mmol) was added to a solution of(S)-4-(benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one)(10 mg, 0.021 mmol) in CH₂Cl₂ (0.6 mL), and the solution was stirred atambient temperature for 1.5 h under N₂. The reaction mixture wasconcentrated under reduced pressure to provide the title compound (6.0mg, 56%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.59-7.56 (m, 2H),7.47-7.45 (m, 3H), 7.42-7.39 (m, 2H), 7.37-7.34 (m, 1H), 7.06 (dd,J=8.5, 2.0 Hz, 1H), 6.29 (dd, J=7.5, 2.5 Hz, 1H), 6.12 (d, J=3.0 Hz,1H), 5.18 (s, 2H), 4.70-4.49 (br m, 2H), 4.28-4.26 (m, 1H), 3.75-3.73(m, 7H), 3.46-3.43 (m, 2H), 3.34-3.33 (m, 2H), 2.46-2.43 (m, 1H),2.21-2.08 (m, 2H), 1.91-1.86 (m, 1H); ESI MS m/z 469 [M+H]⁺; HPLC(Method A) 93.8% (AUC), t_(R)=13.5 min.

Example 131 Preparation of4-(4-Methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride c) tert-Butyl7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

tert-Butyl-7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.19 g, 0.54 mmol), 4-(4-methoxyphenyl)pyridin-2(1H)-one (90 mg, 0.45mmol) and Cs₂CO₃ (0.16 g, 0.49 mmol) were suspensed in DMSO (2.0 mL) anddegassed under vacuum for 15 min. The system was then flushed with Arand 8-hydroxyquinoline (19 mg, 0.13 mmol) and copper iodide (0.10 g,0.54 mmol) were added. The degassing/Ar flushing process was repeatedtwice more, and the reaction mixture was heated at 133° C. for 18 hunder N₂. The suspension was cooled, diluted with 20% NH₄OH/MeOH (25 mL)and stirred at ambient temperature for 30 min. The suspension wasfurther diluted with CH₂Cl₂ (100 mL). The solution was filtered throughsilica gel and concentrated under reduced pressure. The concentrate wasdiluted with CH₂Cl₂ and washed with brine (3×25 mL). The organic phasewas dried over Na₂SO₄, filtered and concentrated to dryness. Flashcolumn chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 10 column volumes, increased to 50:50 over20 column volumes and then hold for 5 column volumes) gave the titlecompound (75 mg, 34%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.60(d, J=9.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.37(d, J=1.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.86(d, J=2.0 Hz, 1H), 6.50 (dd, J=7.0, 2.0 Hz, 1H), 4.66-4.64 (m, 2H), 3.87(s, 3H), 3.85-3.84 (m, 2H), 3.64 (s, 3H), 2.84-2.83 (m, 2H), 1.50 (s,9H).

b)4-(4-Methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(74 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) under N₂ and stirred for 2 h atambient temperature. The mixture was concentrated, and the residue waspartitioned between CH₂Cl₂ and saturated NaHCO₃ solution. The organicphase was removed, and the aqueous phase was extracted with CH₂Cl₂ (4×25mL). The combined organic extracts were washed with brine (25 mL), driedover Na₂SO₄ and concentrated under reduced pressure. Flash columnchromatography (12 g ISCO CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for5 column volumes to 0:100 over 20 column volumes and hold for 5 columnvolumnes) yielded the title compound (46 mg, 78%) as a yellow solid: ¹HNMR (500 MHz, CDCl₃) δ 7.60 (d, J=9.0 Hz, 2H), 7.50-7.46 (m, 2H), 7.36(d, J=2.0 Hz, 1H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H),6.86 (d, J=1.5 Hz, 1H), 6.49 (dd, J=7.0, 2.0 Hz, 1H), 4.08 (s, 2H), 3.87(s, 3H), 3.63 (s, 3H), 3.27 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.5 Hz, 2H).g, 0.96 mmol) and Cs₂CO₃ (0.35 g, 1.1 mmol) were suspensed in DMSO (5.6mL), and the resulting suspension was degassed under vacuum for 15 min.The system was then flushed with Ar, and 8-hydroxyquinoline (42 mg, 0.29mmol) and copper iodide (0.22 g, 1.2 mmol) were added. The evacuation/Arflushing process was repeated twice more, and the reaction mixture washeated at 130° C. for 18 h under N₂. The suspension was cooled, dilutedwith 20% NH₄OH/MeOH (10 mL) and stirred at ambient temperature for 30min. The reaction was further diluted with CH₂Cl₂ (100 mL). The solutionwas filtered through silica gel and concentrated. The concentrate wasdiluted with CH₂Cl₂ and washed with brine (4×20 mL). The organic phasewas dried over Na₂SO₄ and concentrated to dryness under reducedpressure. Flash column chromatography (12 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 50:50 over 20 column volumes and then hold for 5 columnvolumes, increase to 0:100 over 10 column volumes and hold for 5 columnvolumes) gave the title compound (0.25 g, 52%) as a yellow film: ¹H NMR(500 MHz, CDCl₃) δ 7.54 (d, J=8.0 Hz, 1H), 7.42 (d, J=6.5 Hz, 1H), 7.39(d, J=1.5 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.10 (d, J=7.0 Hz, 1H),6.82-6.80 (m, 2H), 6.60 (d, J=1.5 Hz, 1H), 6.24 (dd, J=6.5, 1.5 Hz, 1H),4.67-4.65 (m, 2H), 3.86-3.83 (m, 5H), 3.65 (s, 3H), 2.93 (m, 3H),2.82-2.84 (m, 2H), 1.50 (s, 9H).

b)4-(4-Methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl7-(4-(4-methoxy-2-methylphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.25 g, 0.50 mmol) in CH₂Cl₂ (2.0 mL) under N₂ and stirred for 1 h. Thereaction mixture was made basic with saturated NaHCO₃ solution and theresultion solution was extracted with CH₂Cl₂ (3×25 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure. Flash column

c)4-(4-Methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

2 N HCl in Et₂O (0.12 mL, 0.24 mmol) was added to a solution of4-(4-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(45 mg, 0.12 mmol) in CH₂Cl₂ (2.0 mL), and the solution was stirred atambient temperature for 2.5 h under N₂. The reaction mixture wasconcentrated, partially diluted with H₂O and lyophilized to provide thetitle compound (46 mg, 95%) as a yellow powder: ¹H NMR (500 MHz,DMSO-d₆) δ 9.26 (br s, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.70 (d, J=7.0 Hz,1H), 7.60-7.57 (m, 2H), 7.09-7.06 (m, 3H), 6.73 (d, J=2.0 Hz, 1H), 6.68(dd, J=7.5, 2.0 Hz, 1H), 4.37-4.35 (m, 2H), 3.83 (s, 3H), 3.70 (s, 3H),3.54-3.53 (m, 2H), 3.10 (t, J=6.0 Hz, 2H); ESI MS m/z 386 [M+H]⁺.

Example 132 Preparation of4-(4-Methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-(4-(4-methoxy-2-methylphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

tert-Butyl-7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.35 g, 0.96 mmol), 4-(4-methoxy-2-methylphenyl)pyridin-2(1H)-one (0.21chromatography (12 g ISCO CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for5 column volumes to 0:100 over 20 column volumes and hold for 40 columnvolumes) yielded the title compound (0.16 g, 80%) as an off-white film:¹H NMR (500 MHz, CDCl₃) δ 7.50 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.0 Hz,1H), 7.38 (m, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.07 (dd, J=8.5, 2.0 Hz, 1H),6.82-6.80 (m, 2H), 6.60 (d, J=1.5 Hz, 1H), 6.23 (dd, J=7.0, 1.5 Hz, 1H),4.09 (s, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 2.77 (t, J=5.5 Hz, 2H), 2.27(t, J=6.0 Hz, 2H), 2.39 (s, 3H).

c)4-(4-Methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

2 N HCl in Et₂O (0.40 mL, 0.80 mmol) was added to a solution of4-(4-methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(0.16 g, 0.40 mmol) in CH₂Cl₂ (1.5 mL), and the solution was stirred atambient temperature for 1 h under N₂. The solids were collected byfiltration, washed with Et₂O and dried to yield the title compound (0.15g, 85%) as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (br s,2H), 7.67 (d, J=7.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.27 (d, J=2.0 Hz,1H), 7.25 (d, J=8.5 Hz, 1H), 7.10 (dd, J=8.5, 2.0 Hz, 1H), 6.92 (d,J=2.5 Hz, 1H), 6.88 (dd, J=8.0, 2.5 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H),6.34 (dd, J=7.0, 2.0 Hz, 1H), 4.36-4.34 (m, 2H), 3.79 (s, 3H), 3.71 (s,3H), 3.53-3.52 (m, 2H), 3.10 (t, J=6.0 Hz, 2H), 2.35 (s, 3H); ESI MS m/z400 [M+H]; HPLC (Method A) 95.8% (AUC), t_(R)=14.5 min.

Example 133 Preparation of(4-Benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl7-bromo-9-(difluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate

Sodium hydride (60% in mineral oil, 0.347 g, 8.71 mmol) was added to asolution of tert-butyl7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (2.04 g,5.81 mmol) in DMF (20 mL) at room temperature under N₂ and stirred for30 minutes. Difluoroiodomethane (11.5 mL), which had been condensed witha cold finger into a separate flask, was added via syringe. The reactionwas sealed with a rubber septum and stirred overnight at ambienttemperature. The mixture was quenched with H₂O. EtOAc was added and themixture was stirred for 40 minutes. The mixture was extracted with EtOAc(3×40 mL), and the combined organic extracts were washed with brine(2×20 mL), dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (40+M Biotage column, hexanes/(4:1 hexanes/EtOAc),100:0 to 0:100) provided the title compound (0.93 g, 40%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.62 (s, 1H), 7.17 (t, J=56.0 Hz, 1H),7.33 (m, 2H), 4.71 (s, 2H), 3.75 (m, 2H), 2.74 (s, 2H), 1.50 (s, 9H).

b) tert-Butyl7-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-9-(difluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate

tert-Butyl7-bromo-9-(difluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate(0.936 g, 2.33 mmol), 4-benzyloxypyridone (0.469 g, 2.33 mmol), Cs₂CO₃(0.834 g, 2.57 mmol) and H₂O (1 drop) were diluted with DMSO (10.4 mL)and argon was bubbled through the suspension for 10 minutes.8-Hydroxyquinoline (0.101 g, 0.699 mmol) and copper iodide (133 mg,0.699 mmol) were added, and the resulting suspension was placed undervacuum for 15 min. The system was flushed with argon. Thedegassing/argon flushing process was repeated a total of three times.The reaction mixture was heated to 130° C. for 18 h and stirred underargon. The suspension was cooled. A solution of 20% NH₄OH in MeOH (40mL) was added, and the resulting mixture was stirred for 1 h. Themixture was diluted with CH₂Cl₂ and filtered through celite. Thefiltrate was washed with brine (3×25 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (40+M Biotagecolumn, (20% EtOAc in hexanes)/(50% EtOAc in hexanes)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0:0 to 0:100:0 over 1.2 L then 0:100:0 to0:0:100 over 1.2 L) gave the title compound (0.41 g, 33%) as a yellowfoam: ¹H NMR (500 MHz, DMSO-d₆) δ 8.10 (t, J=58.0 Hz, 1H), 7.74 (d,J=1.4 Hz, 1H), 7.60 (d, J=3.2 Hz, 1H), 7.58 (d, J=3.9 Hz, 1H), 7.47-7.35(m, 5H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 6.12 (dd, J=7.6, 2.6 Hz, 1H),5.99 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.72 (m, 2H), 4.03 (s, 2H), 3.70(m, 2H), 1.44 (s, 9H).

c)(4-Benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

2 N HCl in Et₂O (15.0 mL) was added to a solution of tert-butyl7-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-9-(difluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate(0.39 g, 0.75 mmol) in 1:1 MeOH/CH₂Cl₂ (5 mL). The reaction was stirredat ambient temperature for 2 h under N₂. The reaction was diluted withEt₂O, and the resulting solids were collected by filtration to yield thetitle compound (0.31 g, 92%) as a yellow solid: mp 220-230° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.60 (br s, 2H), 8.11 (t, J=58.0 Hz, 1H), 7.78 (d,J=1.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.48-7.36(m, 5H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=7.5, 2.5 Hz, 1H),5.99 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.52 (m, 2H), 3.49-3.48 (m, 2H),2.99 (m, 2H); ESI MS m/z 422 [M+H]⁺; HPLC (Method A) 96.5% (AUC),t_(R)=14.4 min.

Example 134 Preparation of(4-Benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a)(4-Benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

(4-Benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(83 mg, 20 mmol) and 37% aqueous formaldehyde (22 μL, 0.30 mmol) weredissolved in 1:1 CH₂Cl₂/MeOH (1.0 mL) and stirred at ambient temperaturefor 45 min. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added,and the resulting suspension was stirred at ambient temperature for 15min. The suspension was concentrated, and the residue was diluted withsaturated NaHCO₃ solution. The aqueous solution was extracted withCH₂Cl₂. The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (10 g BiotageSNAP column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) gavethe title compound (57 mg, 67%) as a clear oil. ESI MS m/z 436 [M+H]⁺;HPLC (Method A) 98.9% (AUC), t_(R)=14.3 min.

b)(4-Benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

A solution of(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(58 mg, 0.13 mmol) in CH₂Cl₂ (1.0 mL) was treated with anhydrous 1.0 MHCl in diethyl ether (0.13 mL, 0.13 mmol). The reaction was stirred atambient temperature for 1 h, and the solids were collected and dried toyield the title compound (53 mg, 86%) as a yellow solid: mp 250-256° C.;¹H NMR (500 MHz, DMSO-d₆) δ 10.89 (br s, 1H), 8.15 (t, J=58.0 Hz, 1H),7.82 (d, J=1.5 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H),7.47-7.36 (m, 5H), 7.23 (dd, J=8.4, 1.5 Hz, 1H), 6.14 (dd, J=7.6, 2.7Hz, 1H), 6.00 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.77 (m, 1H), 4.55 (m,1H), 3.76-3.75 (m, 1H), 3.45-3.40 (m, 1H), 3.07-3.02 (m, 5H); ESI MS m/z436 [M+H]⁺; HPLC (Method A) 98.9% (AUC), t_(R)=14.4 min.

Example 135 Preparation of4-(2-Fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(2-Fluoro-4-methoxyphenyl)-2-methoxypyridine

4-Bromo-2-methoxypyridine (1.39 g, 7.42 mmol),2-fluoro-4-methoxyphenylboronic acid (2.40 g, 14.1 mmol), K₂CO₃ (2.05 g,14.8 mmol) and bis(triphenylphosphine) palladium(II) chloride(Pd(PPh₃)₂Cl₂) (52 mg, 0.74 mmol) were stirred in DMSO (8.5 mL) undervacuum for 20 min. The flask was flushed with argon and the mixture washeated to 90° C. for 3 h. Upon cooling, the mixture was diluted withbrine, and the aqueous solution was extracted with CH₂Cl₂ (3×50 mL). Thecombined organic extracts were washed with water (3×20 mL), dried overNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(40+M Biotage column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 to80:20) provided the title compound (0.98 g, 57%) as a yellow oil: ¹H NMR(500 MHz, CDCl₃) δ 8.20 (d, J=5.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.07 (d,J=5.4 Hz, 1H), 6.93 (s, 1H), 6.80 (dd, J=8.6, 2.5 Hz, 1H), 6.74 (dd,J=12.6, 2.5 Hz, 1H), 3.99 (s, 3H), 3.85 (s, 3H).

b) 4-(2-Fluoro-4-methoxyphenyl)pyridin-2(1H)-one

4-(2-Fluoro-4-methoxyphenyl)-2-methoxypyridine (1.34 g, 5.72 mmol) wasstirred in concentrated hydrochloric acid (25.5 mL) at reflux for 18 h.The reaction was cooled to 0° C. and neutralized with solid NaOH. Theresulting solids were collected by filtration and dried under vacuum toyield the title compound (1.09 g, 87%) as a light brown solid: ¹H NMR(300 MHz, DMSO-d₆) δ 7.52-7.38 (m, 2H), 6.97-6.85 (m, 2H), 6.42-6.33 (m,2H), 3.80 (s, 3H); ESI MS m/z 220 [M+H]⁺.

c)tert-Butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

Following the procedure of Example 133 (step b), but substituting4-(2-fluoro-4-methoxyphenyl)pyridin-2(1H)-one (359 mg, 1.64 mmol) for4-benzyloxypyridone, the title compound (288 mg, 41%) was prepared as ayellow foam: ¹H NMR (500 MHz, DMSO-d₆) δ 7.71 (d, J=7.1 Hz, 1H), 7.61(m, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.04-6.99 (m,2H), 6.94 (dd, J=6.9, 2.5 Hz, 1H), 6.61 (s, 1H), 6.51-6.50 (m, 1H), 4.64(s, 2H), 3.84 (s, 3H), 3.69-3.67 (m, 5H), 2.74-2.72 (m, 2H), 1.45 (s,9H).

d)4-(2-Fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution oftert-butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(0.28 g, 0.56 mmol) in CH₂Cl₂ (5 mL) under argon and stirred for 1 h.The mixture was concentrated, and the residue was partitioned betweenCH₂Cl₂ and saturated NaHCO₃ solution. The organic phase was removed, andthe aqueous phase was extracted with CH₂Cl₂. The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressure.Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂Owith 0.05% TFA and CH₃CN with 0.05% TFA) provided the title compound (87mg, 39%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.71 (d, J=7.1Hz, 1H), 7.61 (m, 1H), 7.49-7.46 (m, 2H), 7.02-6.99 (m, 2H), 6.93 (dd,J=8.7, 2.1 Hz, 1H), 6.60 (s, 1H), 6.50 (d, J=7.1 Hz, 1H), 3.96 (m, 2H),3.84 (s, 3H), 3.61 (s, 3H), 3.01-2.99 (m, 2H), 2.66 (m, 2H); ESI MS m/z404 [M+H]⁺.

e)4-(2-Fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

A solution of4-(2-fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(80 mg, 0.20 mmol) in CH₂Cl₂ (2.6 mL) was treated with anhydrous 1.0 MHCl in diethyl ether (0.22 mL, 0.22 mmol). The reaction was stirred atambient temperature for 1 h, and then the solids were collected byfiltration and dried to yield the title compound (68 mg, 77%) as ayellow solid: mp 290-292° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (s, 2H),7.71 (d, J=7.2 Hz, 1H), 7.62-7.58 (m, 3H), 7.10 (dd, J=8.3, 1.8 Hz, 1H),7.01 (dd, J=13.2, 2.4 Hz, 1H), 6.94 (dd, J=8.6, 2.3 Hz, 1H), 6.62 (s,1H), 6.53-6.52 (m, 1H), 4.48 (s, 2H), 3.95 (s, 3H), 3.69 (s, 3H),3.45-3.44 (m, 2H), 3.00-2.97 (m, 2H); ESI MS m/z 404 [M+H]⁺; HPLC(Method A)>99% (AUC), t_(R)=14.6 min.

Example 136 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-fluoro-4-methoxyphenyl)pyridin-2(1H)-onehydrochloride a)1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-fluoro-4-methoxyphenyl)pyridin-2(1H)-one

Following the procedure of Example 134 (step a), but substituting4-(2-fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(57 mg, 0.14 mmol) for(4-benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one,the title compound (35 mg, 59%) was provided as an off-white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 7.71 (d, J=7.0 Hz, 1H), 7.61 (m, 1H), 7.51 (d,J=1.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.02-6.99 (m, 2H), 6.94 (dd,J=8.6, 2.4 Hz, 1H), 6.60 (s, 1H), 6.53-6.52 (m, 1H), 3.84 (s, 3H), 3.62(m, 5H), 2.74-2.70 (m, 4H), 2.46 (s, 3H).

b)1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-fluoro-4-ethoxyphenyl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 134 (step b), but substituting1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-fluoro-4-methoxyphenyl)pyridin-2(1H)-one(35 mg, 0.84 mmol) for(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one,the title compound (33 mg, 87%) was provided as a yellow solid: mp290-294° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.71 (s, 1H), 7.71 (d, J=7.2Hz, 1H), 7.63-7.59 (m, 3H), 7.11 (dd, J=8.3, 1.6 Hz, 1H), 7.01 (dd,J=13.2, 2.4 Hz, 1H), 6.94 (dd, J=8.7, 2.4 Hz, 1H), 6.62 (s, 1H),6.53-6.52 (m, 1H), 4.80-4.77 (m, 1H), 4.45-4.43 (m, 1H), 3.84 (s, 3H),3.73 (br s, 1H), 3.68 (s, 3H), 3.42-3.34 (m, 1H), 3.07-3.06 (m, 2H),3.00 (s, 3H); ESI MS m/z 418 [M+H]⁺; HPLC (Method A) 97.0% (AUC),t_(R)=14.0 min.

Example 137 Preparation of4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide

Imidazo[1,2-a]pyridine-2-ylmethanol (3.01 g, 20.3 mmol) was partiallydissolved in 5:1 dioxane/DMF (30 mL) and the resulting slurry was addedslowly to a stirring suspension of NaH (60% in mineral oil, 0.812 g,16.9 mmol) in dioxane (29 mL). The resulting mixture was heated to 60°C. for 15 min. 4-Chloropyridine-N-oxide (1.5 g, 11.5 mmol) was added andthe reaction mixture was heated for 1 h at 110° C. Upon cooling, themixture was diluted with methylene chloride and a 20% NH₄OH in MeOHsolution. The resulting suspension was filtered through a silica gelplug using CH₂Cl₂ (200 mL) and 20% 4:1 MeOH/NH₄OH in CH₂Cl₂ (500 mL).The filtrate was collected and concentrated under reduced pressure.Flash chromatography (120 g ISCO column, CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100 over 60 min) provided the titlecompound (1.5 g, 30%) as an orange-brown solid: ¹H NMR (300 MHz, CD₃OD)δ 8.42 (m, 1H), 8.24-8.22 (m, 2H), 7.97 (d, J=0.5 Hz, 1H), 7.54 (dd,J=9.1, 0.7 Hz, 1H) 7.37-7.32 (m, 1H), 7.27-7.25 (m, 2H), 6.94 (m, 1H),5.37 (s, 2H).

b) 4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine-2(1H)-one

4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide (1.50 g, 6.25mmol) was heated at 140° C. in acetic anhydride (18 mL) for 2 h. Themixture was concentrated and heated at 80° C. for 2 h in 1:1 MeOH/H₂O(50 mL). The resulting black solution was concentrated. The material wasthen partially dissolved in iPrOH (20 mL). Et₂O (70 mL) was added, andthe mixture was allowed to sit at ambient temperature for 1 h. Theresulting solids were collected by filtration and washed with Et₂O toyield the title compound (951 mg, 63%) as a dark brown solid: ¹H NMR(300 MHz, DMSO-d₆) δ 11.08 (br s, 1H), 8.54 (m, 1H), 8.01 (s, 1H), 7.53(d, J=9.0 Hz, 1H), 7.26-7.23 (m, 2H), 6.90 (m, 1H), 5.89-5.87 (m, 2H),5.14 (s, 2H).

c)tert-Butyl-7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(0.328 g, 0.898 mmol),4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine-2(1H)-one (0.240 g, 0.998mmol) and Cs₂CO₃ (0.358 g, 1.09 mmol) were suspended in DMSO (4.0 mL),and argon was bubbled through the system for 10 minutes.8-Hydroxyquinoline (43.4 mg, 0.299 mmol) and copper iodide (228 mg, 1.20mmol) were added, and resulting suspension was placed under vacuum for15 min. The system was flushed with argon. The evacuation/argon flushingprocess was repeated a total of three times. The reaction mixture washeated at 130° C. for 18 h under argon. The mixture was cooled, and asolution of 20% NH₄OH in MeOH (40 mL) was added. The resulting mixturewas stirred for 1 h. The mixture was diluted with CH₂Cl₂ and filteredthrough a silica gel plug. The filtrate was collected and concentrated.The residue was diluted with CH₂Cl₂, washed with brine (3×25 mL), driedover Na₂SO₄ and concentrated under reduced pressure. Purification byflash column chromatography (80 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 80:20 to 0:100:0 over 10column volumes and then hold for 8 column volumes) gave the titlecompound (0.190 g, 40%) as a yellow foam: ¹H NMR (500 MHz, DMSO-d₆) δ8.12 (d, J=6.8 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.52 (d,J=8.3 Hz, 1H), 7.31-7.29 (m, 2H), 7.22-7.19 (m, 1H), 7.02 (dd, J=8.3,1.7 Hz, 1H), 6.83-6.80 (m, 1H), 6.17 (d, J=2.7 Hz, 1H), 6.07 (dd, J=7.6,2.7 Hz, 1H), 5.25 (s, 2H), 4.64 (m, 2H), 3.75 (m, 2H), 3.63 (s, 3H),2.80 (m, 2H), 1.52 (s, 9H)— ESI MS m/z 526 [M+H]⁺.

d)4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

Following the procedure of Example 135 (step d), but substitutingtert-butyl-7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(190 mg, 362 mmol) fortert-butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate,the title compound (0.105 g, 68%) was prepared as a yellow film: ¹H NMR(500 MHz, CD₃OD) δ 8.45-8.43 (m, 1H), 7.98 (s, 1H), 7.59-7.54 (m, 3H),7.41 (d, J=1.8 Hz, 1H), 7.37-7.33 (m, 1H), 7.02 (dd, J=8.3, 1.8 Hz, 1H),6.96-6.94 (m, 1H), 6.29 (dd, J=7.6, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H),5.31 (s, 2H), 3.96 (s, 2H), 3.68 (s, 3H), 3.42 (t, J=6.0 Hz, 2H), 3.00(t, J=6.0 Hz, 2H); ESI MS m/z 426 [M+H].

e)4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one-hydrochloride

Following the procedure of Example 134 (step b), but substituting4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(102 mg, 0.240 mmol) for(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one,the title compound (95 mg, 86%) was prepared as a yellow solid: ¹H NMR(500 MHz, CD₃OD) δ 8.81 (d, J=7.0, 1.0 Hz, 1H), 8.38 (s, 1H), 8.02-7.99(m, 1H), 7.92 (d, J=9.5 Hz, 1H), 7.66-7.62 (m, 2H), 7.52-7.49 (m, 1H),7.46 (s, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.33 (dd, J=7.5, 3.0 Hz, 1H), 6.23(d, J=3.0 Hz, 1H), 5.50 (s, 2H), 4.55 (s, 2H), 3.72 (s, 3H), 3.60 (t,J=6.0 Hz, 2H), 3.14-3.12 (m, 2H); ESI MS m/z 426 [M+H]⁺; HPLC (Method A)98.5% (AUC), t_(R)=9.2 min.

Example 138 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-onehydrochloride a)1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one

Following the procedure of Example 134 (step a), but substituting4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(57 mg, 0.14 mmol) for(4-benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one,the title compound (25 mg, 62%) was prepared as a yellow solid: ¹H NMR(500 MHz, DMSO-d₆) δ 7.54 (d, J=7.5 Hz, 1H), 7.47-7.36 (m, 7H), 6.95(dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=3.0Hz, 1H), 5.15 (s, 2H), 3.64 (m, 4H), 3.18-3.16 (m, 1H), 3.05-3.02 (m,1H), 2.90-2.84 (m, 4H), 2.42-2.39 (m, 1H), 2.00-1.92 (m, 1H).

b)1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 134 (step b), but substituting1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one(25 mg, 0.056 mmol) for(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one,the title compound (27 mg, 98%) was prepared as a yellow solid: ¹H NMR(500 MHz, DMSO-d₆) δ 10.91 (br s, 1H), 8.86 (d, J=6.0 Hz, 1H), 8.39 (s,1H), 7.87-7.79 (m, 2H), 7.61 (d, J=7.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H),7.51 (s, 1H), 7.37-7.35 (m, 1H), 7.01 (dd, J=8.5, 1.0 Hz, 1H), 6.15-6.11(m, 2H), 5.42 (s, 2H), 4.77 (d, J=15.0 Hz, 1H), 4.43 (dd, J=14.0, 6.0Hz, 1H), 3.80-3.77 (m, 1H), 3.66 (s, 3H), 3.41-3.39 (m, 1H), 3.08-3.04(m, 2H), 2.99 (s, 3H); ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 97.1%(AUC), t_(R)=9.8 min.

Example 139 Preparation of1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-onehydrochloride a) 4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine 1-oxide

Following the procedure of Example 137 (step a), but substitutingimidazo[1,2-a]pyridine-6-ylmethanol (2.91 g, 19.6 mmol) forimidazo[1,2-a]pyridine-2-ylmethanol, the title compound (1.69 g, 42%)was prepared as an orange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s,1H), 8.13-8.10 (m, 2H), 7.97 (s, 1H), 7.60-7.59 (m, 2H), 7.30 (dd,J=9.3, 1.7 Hz, 1H), 7.14-7.11 (m, 2H), 5.18 (s, 2H).

b) 4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine-2(1H)-one

4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine 1-oxide (1.69 g, 7.04mmol) was heated at 140° C. in acetic anhydride (20 mL) for 4 h. Themixture was concentrated and heated at 80° C. for 3 h in a mixture of1:1 MeOH/H₂O (50 mL). The resulting solution was concentrated. Theresidue was partially dissolved in iPrOH (75 mL). Et₂O (200 mL) wasadded, and the mixture was allowed to sit at ambient temperature for 1h. The resulting solids were collected by filtration, washed with Et₂Oand dried under reduced pressure. The solids were again subjected toiPrOH and Et₂O, and the solids were removed by filtration. The filtratewas concentrated to afford the title compound (0.47 g, 28%) as a darkbrown solid: ¹H NMR (300 MHz, CD₃OD) δ 8.60 (d, J=0.7 Hz, 1H), 7.87 (d,J=0.6 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.57 (s, 1H), 7.40-7.27 (m, 2H),6.18 (dd, J=7.3, 2.5 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.13 (s, 2H).

c)tert-Butyl-7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

Following the procedure of Example 133 (step b), but substituting4-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine-2(1H)-one (218 mg, 0.901mmol) for 4-benzyloxypyridone, the title compound (112 mg, 26%) wasprepared as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.25 (s, 1H),7.68-7.65 (m, 2H), 7.64-7.61 (m, 1H), 7.53-7.52 (m, 1H), 7.33 (d, J=7.6Hz, 1H), 7.28-7.26 (m, 1H), 7.22 (dd, J=9.3, 1.5 Hz, 1H), 7.01 (dd,J=8.2, 1.8 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 6.03 (dd, J=7.5, 2.7 Hz,1H), 5.06-5.04 (m, 2H), 4.70-4.57 (m, 2H), 3.75 (m, 2H), 3.62 (s, 3H),2.79 (m, 2H), 1.51 (s, 9H).

d)4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 135 (step d), but substitutingtert-butyl-7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(112 mg, 0.213 mmol) fortert-butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate,the crude title compound was prepared. Preparative HPLC (Phenomenex LunaC18 (2), 250.0×21.2 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with0.05% TFA) yielded the title compound (12 mg, 13%) as an off-white film:¹H NMR (500 MHz, CDCl₃) δ 8.24 (s, 1H), 7.67-7.65 (m, 2H), 7.59 (s, 1H),7.53 (d, J=8.3 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.26 (m, 1H overlappingwith solvent), 7.22 (dd, J=9.3, 1.6 Hz, 1H), 7.00 (dd, J=8.3, 1.8 Hz,1H), 6.11 (d, J=2.7 Hz, 1H), 6.03 (dd, J=7.6, 2.7 Hz, 1H), 5.04 (s, 2H),4.04 (s, 2H), 3.57 (s, 3H), 3.17 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz,2H).

e)4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

Following the procedure of Example 134 (step b), but substituting4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(12 mg, 0.028 mmol) for(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one,the title compound (14 mg, 100%) was prepared as a light yellow solid:¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (br s, 2H), 9.01 (s, 1H), 8.33 (s, 1H),8.11 (s, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.61 (d,J=7.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.00 (dd,J=8.4, 1.7 Hz, 1H), 6.13 (dd, J=7.6, 2.7 Hz, 1H), 6.08 (d, J=2.7 Hz,1H), 5.31 (s, 2H), 4.46 (m, 2H), 3.67 (s, 3H), 3.44 (m, 2H), 2.97 (t,J=5.7 Hz, 2H); ESI MS m/z 426 [M+H]⁺; HPLC (Method A)>99% (AUC),t_(R)=9.7 min.

Example 140 Preparation of4-(Benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) (3-Bromo-4-fluorophenyl)hydrazine hydrochloride

A solution of sodium nitrite (4.2 g, 60 mmol) was added drop-wise to amixture of 3-bromo-4-fluoroaniline (11.2 g, 58.9 mmol) and concentratedHCl (30 mL, 0.36 M) at 0° C. over 30 min. The resulting clear solutionwas stirred for 45 min, and a solution of SnCl₂.2H₂O (27 g, 120 mmol) inconcentrated HCl (30 mL) was added drop-wise at 0° C. over 1.5 h. Themixture was stirred for 18 h at room temperature. The resultingprecipitate was collected by filtration and crystallized from ethanol toprovide the title compound (6.2 g, 42%) as a yellow powder: ¹H NMR (300MHz, DMSO-d₆) δ 10.24 (s, 3H), 8.42 (s, 1H), 7.36-7.30 (m, 2H),7.03-6.98 (m, 1H).

b) 7-Bromo-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

A mixture of (3-bromo-4-fluorophenyl)hydrazine hydrochloride (3.0 g, 12mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.48 g, 12.5 mmol) andconcentrated HCl (6.0 mL, 72 mmol) in ethanol (40 mL) was stirred for 18h at reflux. The solvent was removed under reduced pressure, the residuewas suspended in dichloromethane (50 mL), and di-tert-butyl dicarbonate(3.3 g, 15 mmol) and triethylamine (2.1 mL, 30 mmol) were added. Themixture was stirred for 18 h at ambient temperature. The resulting clearsolution was concentrated, and the residue was purified by flashchromatography (silica gel, hexanes/ethyl acetate, 1:0 to 1:1) to affordthe title compound (0.9 g, 20%) as a yellow solid: ¹H NMR (500 MHz,CDCl₃) δ 7.94 (br s, 1H), 7.45 (d, J=5.5 Hz, 1H), 7.14 (br s, 1H), 4.56(br s 2H), 3.81 (br m 2H), 2.81 (br m 2H), 1.57 (s, 9H); ESI MS m/z 369[M+H]⁺.

c) tert-Butyl7-bromo-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Sodium hydride (60% weight dispersion in mineral oil, 150 mg, 3.66 mmol)was added to a solution of tert-butyl7-bromo-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(0.9 g, 2.44 mmol) in 20 ml of DMF, and the mixture was stirred for 40min at ambient temperature. Iodomethane (0.25 mL, 3.66 mmol) was added,and the resulting suspension was stirred for 2 h. The resulting mixturewas concentrated under reduced pressure to ⅓ of initial volume andtreated with water (20 mL). The resulting precipitate was collected byfiltration, sequentially washed with water and diethyl ether and driedunder vacuum to afford the title compound (0.75 g, 83%) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 7.42 (d, J=5.4 Hz, 1H), 7.17 (d, J=9.3Hz, 1H), 4.45 (br s, 2H), 3.81 (br m, 2H), 3.60 (s, 3H), 2.78 (br m,2H), 1.52 (s, 9H); ESI MS m/z 383 [M+H]⁺.

d)4-(Benzyloxy)-1-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one

tert-Butyl7-bromo-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(720 mg, 1.88 mmol), 4-benzyloxypyridone (380 mg, 1.9 mmol) and Cs₂CO₃(680 mg, 2.1 mmol) were suspended in DMSO (8.0 mL) and the resultingsuspension was degassed for 15 min. The system was flushed with Ar. Then8-hydroxyquinoline (87 mg, 0.60 mmol) and copper iodide (114 mg, 0.599mmol) were added. The degassing/Ar flushing process was repeated twicemore, and the reaction mixture was heated at 133° C. for 18 h underargon. The reaction mixture was cooled, diluted with 15% solution ofconcentrated ammonium hydroxide in methanol (25 mL) and stirred atambient temperature for 30 min. The reaction was further diluted withdichloromethane (75 mL). The solution was filtered through silica geland concentrated under reduced pressure. The residue was diluted withCH₂Cl₂ and washed with H₂O (25 mL) and brine (3×50 mL). The combinedorganics were dried over Na₂SO₄ and concentrated to dryness. The crudematerial was purified by flash chromatography (silica gel, (1:1hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol concentrated ammoniumhydroxide), 1:0 to 0:1) to afford crude tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(280 mg) as a yellow oil. This oil was dissolved in dichloromethane (3mL) and TFA (1 mL) was added. The reaction mixture was stirred atambient temperature for 1 h, concentrated and dried under vacuumovernight to provide the title compound (200 mg), which was used in thenext step without further purification: ESI MS m/z 404 [M+H]⁺.

e)4-(Benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-(benzyloxy)-1-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(100 mg, 0.26 mmol) in dichloromethane/acetic acid (1% acetic acid, 10mL) were sequentially added formaldehyde (37% aqueous solution, 22 μL,0.74 mmol) and NaBH(OAc)₃ (316 mg, 1.49 mmol). The reaction mixture wasstirred at room temperature for 2.5 h. The mixture was concentratedunder reduced pressure, and the residue was dissolved in CH₂Cl₂. Theorganic layer was washed with H₂O and 5% aqueous LiCl, dried overNa₂SO₄, filtered and concentrated. Purification by flash chromatography(silica gel, CH₂Cl₂/(10:1:0.1 CH₂Cl₂/MeOH/NH₄OH), 0:1 to 1:1) gave4-(benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one(78 mg, 38%) as a yellow solid. The free base was converted to the HClsalt using 1.25M HCl in methanol providing the title compound (75 mg,95%) as a off-white solid: ¹H NMR (300 MHz, CD₃OD) δ 7.53-7.33 (m, 7H),7.27 (d, J=10.5 Hz, 1H), 7.28 (dd, J=7.8, 2.4 Hz, 1H), 6.10 (d, J=2.7Hz, 1H), 5.17 (s, 2H), 3.79 (br s, 2H), 3.67 (s, 3H), 3.03-3.00 (m, 4H),2.64 (s, 3H); ESI MS m/z 418 [M+H]⁺; HPLC (Method A) 95.7% (AUC),t_(R)=14.5 min.

Example 141 Preparation of4-(Benzyloxy)-1-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride a) 2-(6-Bromo-5-fluoro-1H-indol-3-yl)ethanamine

4,4-Diethoxybutan-1-amine (4.72 g, 29.3 mmol) was added to(3-bromo-4-fluorophenyl)hydrazine hydrochloride (6.4 g, 27 mmol). Theresulting mixture in an open round bottom flask was placed into apreheated oil bath at 180° C. The mixture was stirred at 180° C. for 2.5h and then cooled to 120° C. Methanol (300 mL) was added, and themixture was stirred at ambient temperature for 18 h. The resultingsuspension was filtered through a silica gel plug, and the silica gelwas then washed with methanol (5×300 mL). The combined methanolfractions were concentrated under vacuum to provide the crude titlecompound (8.1 g) as a yellow solid, which was used in the next stepwithout further purification: ESI MS m/z 257 [M+H]⁺.

b) tert-Butyl7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

Glyoxylic acid (8.6 g, 95 mmol) was added to a solution of2-(6-bromo-5-fluoro-1H-indol-3-yl)ethanamine (8.1 g 31 mmol) in 2 N HCl(150 ml), and the pH of the resulting solution was adjusted to pH 3.5with 6 N NaOH solution. The reaction mixture was stirred at ambienttemperature for 18 h. The solution was adjusted to pH 5.5 with 6 N NaOHsolution. The resulting precipitate was collected by filtration anddried under vacuum to afford a yellow solid. The yellow solid wassuspended in 2 N HCl (100 mL), and the resulting mixture was stirred atreflux for 4.5 h. The reaction mixture was cooled to ambient temperatureand was adjusted to pH 10 by addition of 2 N sodium hydroxide solution.The resulting precipitate was collected by filtration and dried undervacuum to afford a crude mixture of7-bromo-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and6-bromo-7-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.0 g, 23%)as a yellow solid. The mixture (1.9 g, 7.1 mmol) was suspended indichloromethane (100 mL) and di-tert-butyl carbonate (1.85 g, 8.7 mmol)was added, followed by addition of DMAP (100 mg, 0.82 mmol). Thereaction mixture was stirred at ambient temperature for 18 h andconcentrated under vacuum. The residue was purified twice by columnchromatography (silica gel, hexanes/ethyl acetate, 0:1 to 1:1) to affordthe title compound (300 mg, 12%) as a pale yellow solid: ¹H NMR (300MHz, CDCl₃) δ 7.46 (d, J=5.7 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 4.61 (s,2H), 3.75 (br m, 2H), 2.73 (br m, 2H), 1.56 (s, 9H); ESI MS m/z 369[M+H]⁺.

c) tert-Butyl7-bromo-6-fluoro-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

Sodium hydride (60% weight dispersion in mineral oil, 25 mg, 0.60 mmol)was added to a solution of tert-butyl7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(150 mg, 0.40 mmol) in DMF (10 mL) at room temperature under N₂ andstirred for 1 h at ambient temperature. Methyl iodide (230 mg, 0.16 mL,0.60 mmol) was added, and the reaction mixture was stirred for 1 h. Theresulting mixture was concentrated under reduced pressure toapproximately ⅓ of initial volume and treated with water (20 mL). Theresulting precipitate was collected by filtration, washed with water anddiethyl ether and dried under vacuum to afford the title compound (140mg, 91%) as a yellow powder: ESI MS m/z 383 [M+H]⁺.

d)4-(Benzyloxy)-1-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl7-bromo-6-fluoro-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(160 mg, 0.40 mmol), 4-benzyloxypyridone (80 mg, 0.33 mmol) and Cs₂CO₃(390 mg, 0.38 mmol) were suspended in DMSO (8.0 mL) and degassed undervacuum for 15 min. The system was then flushed with Ar, and8-hydroxyquinoline (30 mg, 0.18 mmol) and copper iodide (80 mg, 0.40mmol) were added. The degassing/Ar flushing process was repeated twice,and the reaction mixture was heated at 133° C. for 18 h under argon. Themixture was cooled, diluted with 15% solution of concentrated ammoniumhydroxide in methanol (25 mL) and stirred at ambient temperature for 30min. The reaction was further diluted with CH₂Cl₂ (75 mL) and filteredthrough silica gel and concentrated. The concentrate was diluted withCH₂Cl₂ and washed with H₂O (25 mL) and brine (3×50 mL). The combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure to dryness. The crude material was purified by flashchromatography (silica gel, (1:1 hexanes/EtOAc)/(10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to 0:1)to afford 75 mg of crude material containing the desired product. Thecrude mixture was dissolved in a mixture of dichloromethane and methanol(1:1, 5 mL), treated with TFA (2 mL) and stirred at ambient temperaturefor 30 min. The solvent was removed under reduced pressure, and theresidue was neutralized by ion-exchange chromatography (SCX-2 column, 5g). Purification by preparatory TLC (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) provided thefree base of the title compound (12 mg, 10%) as a white foam: ESI MS m/z404 [M+H]⁺. The free base was dissolved in methanol (25 mL) and treatedwith a solution of HCl (1.25 M in methanol, 0.1 mL, 0.13 mmol). Thereaction mixture was sonicated for 5 min at ambient temperature. Themixture was concentrated, and the resulting residue was lyophilized fromwater (5 mL) to afford the title compound (14 mg, 8%) as a white powder:¹H NMR (500 MHz, DMSO-d₆) δ 9.56 (br s, 2H), 7.61 (d, J=6.0 Hz, 1H),7.54 (d, J=7.5 Hz, 1H), 7.50-7.37 (m, 6H), 6.14-6.12 (m, 1H), 5.99 (s,1H), 5.16 (s, 2H), 4.46 (br s, 2H), 3.67 (s, 3H), 3.43 (br m, 2H), 2.94(m, 2H); ESI MS m/z 404 [M+H]⁺; HPLC (Method A) 95.7% (AUC), t_(R)=14.8min

Example 142 Preparation of4-(Benzyloxy)-1-(2-ethyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (120 mg, 0.28 mmol) in dichloromethane/acetic acid (1%acetic acid, 10 mL) were sequentially added acetaldehyde (0.50 mL, 13mmol) and NaBH(OAc)₃ (1.0 g, 4.7 mmol). The reaction mixture was stirredat ambient temperature for 1 h. The mixture was concentrated, and theresidue was purified by flash chromatography (silica gel silica gel,(1:1 hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol/concentratedammonium hydroxide), 1:0 to 0:1) to provide4-(benzyloxy)-1-(2-ethyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(120 mg, 72%) as a white solid. The free base was converted to the HClsalt using 1.25 M HCl in methanol, providing the title compound (120 mg,95%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.57 (d, J=7.5Hz, 1H), 7.54-7.34 (m, 7H), 6.97 (d, J=8.0 Hz, 1H), 6.10 (dd, J=7.5, 2.0Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 3.67 (s, 3H), 3.45-3.18 (4H,overlapping with solvent peak), 3.26 (br m, 2H), 2.96 (m, 2H), 1.33 (brm, 3H); ESI MS m/z 414 [M+H]⁺; HPLC (Method A) 95.7% (AUC), t_(R)=14.6min.

Example 143 Preparation of4-(Benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride

2-Bromopropane (1.5 mL, 16 mmol) was added to a mixture of4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onehydrochloride (138 mg, 0.327 mmol) and Cs₂CO₃ (1.2 g, 3.7 mmol) inacetonitrile (25 mL). The mixture was stirred at 55° C. for 72 h. Theresulting mixture was cooled, and the precipitate was filtered off. Themother liquor was concentrated under vacuum. The residue was purified bypreparatory TLC (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to afford4-(benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one.The free base was converted to the HCl salt using 1.25 M HCl in methanolto provide the title compound (26 mg, 19%) as a off white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 10.50 (s, 1H), 7.56 (d, J=4.5 Hz, 2H), 7.52-7.38(m, 6H), 7.01 (dd, J=4.5, 1.0 Hz, 1H), 6.11 (dd, J=4.5, 1.0 Hz, 1H),5.97 (s, 1H), 5.16 (s, 2H), 4.60-4.53 (m, 2H), 3.78-3.70 (m, 2H), 3.70(s, 3H), 3.40-3.28 (m, 1H), 3.18-2.98 (m, 2H), 1.44-1.39 (m, 6H); ESI MSm/z 428 [M+H]⁺; HPLC (Method A) 95.7% (AUC), t_(R)=15.1 min.

Example 144 Preparation of Isopropyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

Following the procedure of Example 143, the title compound (12 mg, 8%)was obtained as a second product as an off-white powder afterlyophilization from acetonitrile/water: ¹H NMR (500 MHz, CDCl₃) δ 7.48(d, J=8.5 Hz, 1H), 7.50-7.32 (m, 7H), 6.99 (d, J=8.5 Hz, 1H), 6.90 (s,1H), 6.34 (d, J=6.5 Hz, 1H), 5.17 (s, 2H), 5.05-5.00 (m, 1H), 4.72-4.58(m, 2H), 3.79 (br m, 2H), 3.76 (s, 3H), 2.82 (m, 2H), 1.42-1.32 (m, 6H);ESI MS m/z 472 [M+H]⁺; HPLC (Method A) 95.7% (AUC), t_(R)=19.9 min.

Example 145 Preparation of4-(Benzyloxy)-3-bromo-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-onehydrochloride

2-Bromopropane (0.25 mL, 2.7 mmol) was added to a solution of4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-onein DMSO (5 mL). The reaction mixture was stirred at 55° C. for 3 d. Themixture was diluted with a saturated solution of sodium bicarbonate andextracted with dichloromethane (3×50 mL). The combined organics werewashed with water and brine, dried over sodium sulfate and concentratedunder reduced pressure. Purification by preparatory TLC (silica gel,10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide)provided the free base of the title compound. The free base wasconverted to the HCl salt using 2.5 M HCl in methanol to afford, afterlyophilization from acetonitrile/water, the title compound (15 mg, 14%)as a yellow solid: ¹H NMR (300 MHz, CD₃OD) δ 7.71 (d, J=7.8 Hz, 1H),7.63 (d, J=8.4, Hz, 1H), 7.53-7.30 (m, 6H), 7.05 (dd, J=7.8, 1.2 Hz,1H), 6.60 (d, J=7.6 Hz, 1H), 5.40 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H),3.62-3.55 (m, 2H), 3.22-3.02 (m, 2H); ESI MS m/z 465 [M+H]⁺; HPLC(Method A) 95.7% (AUC), t_(R)=15.3 min.

Example 146 Preparation of4-(Benzyloxy)-1-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) Di-tert-butyl7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate

To a solution of tert-butyl7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.00 g,2.85 mmol), Boc₂O (683 mg, 3.13 mol) and triethylamine (0.73 mL, 5.7mmol) in methylene chloride (30 mL) at room temperature was added DMAP(50 mg, 0.41 mmol), and the reaction progressed for 18 h. The mixturewas washed with 0.5 N HCl, and the organic phase was removed, dried overNa₂SO₄, filtered and concentrated to dryness. The crude title product(1.25 g, 98%) was recovered as an orange solid: ¹H NMR (500 MHz, CDCl₃)δ 8.37 (br s, 1H), 7.34 (dd, J=8.2, 1.6 Hz, 1H), 7.24 (d, J=8.25 Hz,1H), 4.54 (br s, 2H), 3.73 (m, 2H), 3.07 (t, J=5.6 Hz, 2H), 1.66 (s,9H), 1.50 (s, 9H).

b) tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Prepared from di-tert-butyl7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (1.24 g,2.72 mmol) and 4-benzyloxypyridone (547 mg, 2.72 mmol) according to theprocedure of Example 1 (step c). Purification by flash columnchromatography (silica gel, hexanes/ethyl acetate, 100:0 to 80:20 to50:50 to 25:75 then 0:100) gave the title compound (155 mg, 10%) as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.40 (br s, 1H), 7.44-7.38 (m,5H), 7.30 (d, J=7.5 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 6.82(dd, J=8.2, 1.4 Hz, 1H), 6.12-6.09 (m, 2H), 5.09 (s, 2H), 4.46 (br s,2H), 3.70 (br m, 2H), 2.54 (br m, 2H), 1.50 (s, 9H).

c)4-(Benzyloxy)-1-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

Prepared from tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(150 mg, 0.32 mmol) according to the procedure of Example 1 (step d).Purification by flash column chromatography (4 g ISCO column elutingwith methylene chloride and a methanol/ammonia mixture (10:1); gradient100% methylene chloride to 85% methylene chloride over 30 min) providedthe free-base as a yellow solid. This was converted to the bis-HCl salt(2 N HCl Et₂O in CH₂Cl₂) providing the title compound (36 mg, 26%) as ayellow solid: mp 240° C. dec.; ¹H NMR (500 MHz, CD₃OD) δ 7.65 (d, J=7.5Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 2H), 7.42-7.36 (m,4H), 7.03 (d, J=8.5 Hz, 1H), 6.39 (dd, J=7.6, 2.5 Hz, 1H), 6.21 (d,J=2.5 Hz, 1H), 5.21 (s, 2H), 4.47 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.20(t, J=6.1 Hz, 2H); ESI MS m/z 372 [M+H]⁺; HPLC (Method A) 95.0% (AUC),t_(R)=12.2 min.

Example 147 Preparation of4-(Benzyloxy)-1-(5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl7-bromo-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Prepared from tert-butyl7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (500 mg,1.43 mmol) according to the procedure of Example 1 (step b). Thisprovided the title compound (520 mg, 96%) as a yellow/orange solid: ¹HNMR (500 MHz, CDCl₃) δ 7.36 (s, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.10 (d,J=8.2 Hz, 1H), 4.54 (s, 2H), 3.96 (q, J=7.2 Hz, 2H), 3.76 (br m, 2H),2.71 (br m, 2H), 1.43 (s, 9H), 1.25 (t, J=7.2 Hz, 3H).

b) tert-Butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Prepared from tert-butyl7-bromo-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(500 mg, 1.32 mmol) and 4-benzyloxypyridone (265 mg, 1.32 mmol),according to the procedure of Example 1 (step c). Purification by flashcolumn chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to50:50 to 25:75 then 0:100) gave the title compound (317 mg, 48%) as ayellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.2 Hz, 1H),7.44-7.37 (m, 5H), 7.32-7.29 (m, 2H), 7.04 (d, J=8.0 Hz, 1H), 6.10-6.03(m, 2H), 5.08 (s, 2H), 4.66 (br s, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.86 (brm, 2H), 2.84 (br m, 2H), 1.53 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).

c)4-(Benzyloxy)-1-(5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-onedihydrochloride

Prepared from tert-butyl7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(315 mg, 0.631 mmol) according to the procedure of Example 1 (step d)providing the title compound (207 mg, 74%) as a yellow solid: mp176-181° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.83 (d, J=7.5 Hz, 1H), 7.62-7.57(m, 2H), 7.45-7.40 (m, 5H), 7.09 (dd, J=8.4, 1.6 Hz, 1H), 6.59 (dd,J=7.5, 2.3 Hz, 1H), 6.36 (d, J=2.3 Hz, 1H), 5.28 (s, 2H), 4.49 (s, 2H),4.23 (q, J=7.2 Hz, 2H), 3.68 (t, J=6.1 Hz, 2H), 3.22 (t, J=5.9 Hz, 2H),1.35 (t, J=7.1 Hz, 3H); ESI MS m/z 400 [M+H]; HPLC (Method A)>99% (AUC),t_(R)=13.2 min.

In accordance with further embodiments of the invention, there areprovided the following compounds, which may be synthesized by analogy bythe methods shown and described above:

Name Structure 1-(2-Isobutyryl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

1-(5-Methyl-2-propionyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(4,4,5-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one

N,N,5-Trimethyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxamide

4-((5-Fluoropyridin-2-yl)methoxy)-1-(2-isobutyryl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7- yl)pyridin-2(1H)-one

1-(2-Ethyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-fluoropyridin-2- yl)methoxy)pyridin-2(1H)-one

1-(2-(3-Hydroxy-2,2-dimethylpropanoyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

1-(2-(3-Hydroxy-3-methylbutanoyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

1-(2-(2-Hydroxyacetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)- one

Isopropyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido [3,4-b]indole-2(9H)- carboxylate

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)pyridin- 2(1H)-one

1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)pyridin- 2(1H)-one

2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)pyridazin- 3(2H)-one

2-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)pyridazin- 3(2H)-one

2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-5-(6-(trifluoromethyl)pyridazin-3-yl)pyridazin- 3(2H)-one

2-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-5-(6-(trifluoromethyl)pyridazin-3-yl)pyridazin- 3(2H)-one

2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)- one

2-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)- one

4-(Benzyloxy)-1-(2-isobutyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)- one

4-(Benzyloxy)-1-(2-isobutyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)- one

4-(Benzyloxy)-1-(2-(cyclopropylmethyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin- 2(1H)-one

4-(Benzyloxy)-1-(2-(cyclopropylmethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin- 2(1H)-one

4-(5-Methoxypyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)- one

4-(5-Methoxypyridin-2-yl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)- one

4-(Benzyloxy)-1-(4,4,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(1,1,5-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(1,1,3,3,5-pentamethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)- one

4-(Benzyloxy)-1-(3,3,5-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(methylsulfinyl)phenyl)pyridin-2(1H)-one

1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(methylsulfinyl)phenyl)pyridin-2(1H)-one

1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(methylthio)pyridin-2-yl)pyridin-2(1H)-one

1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(methylthio)pyridin-2-yl)pyridin-2(1H)-one

Binding Assay I for Human Melanin-Concentrating Hormone (MCH₁) receptorEvaluation of the affinity of compounds for the human MCH₁ receptor wasaccomplished in transfected Chinese Hamster Ovary (CHO) cells determinedin a radioligand binding assay, as described in MacDonald et al.,“Molecular characterization of the melanin-concentratinghormone/receptor complex: identification of critical residues involvedin binding and activation”, Mol. Pharmacol., 58:217 (2000). Cellmembrane homogenates (5 μg protein) were incubated for 60 min at 22° C.with 0.1 nM [¹²⁵I][Phe¹³,Tyr¹⁹]-MCH in the absence or presence of thetest compound in a buffer containing 25 mM Hepes/Tris (pH 7.4), 5 mMMgCl₂, 1 mM CaCl₂ and 0.5% bovine serum albumin (BSA). Nonspecificbinding was determined in the presence of 0.1 μM MCH. Followingincubation, the samples were filtered rapidly under vacuum through glassfiber filters (GF/B, Packard) and rinsed several times with an ice-coldbuffer containing 25 mM Hepes/Tris (pH 7.4), 500 mM NaCl, 5 mM MgCl₂, 1mM CaCl₂ and 0.1% BSA using a 96-sample cell harvester (Unifilter,Packard). The filters were dried, then counted for radioactivity in ascintillation counter (Topcount, Packard) using a scintillation cocktail(Microscint 0, Packard).

The results are expressed as a percent inhibition of the controlradioligand specific binding. The IC₅₀ value (concentration causing ahalf-maximal inhibition of control specific binding) and Hillcoefficient (n_(H)) were determined by non-linear regression analysis ofthe competition curve using Hill equation curve fitting. The inhibitionconstant (K_(i)) was calculated from the Cheng Prusoff equation:(K_(i)=IC₅₀/(1+(L/K_(D))), where L=concentration of radioligand in theassay, and K_(D)=affinity of the radioligand for the receptor).

Binding Assay II for Human Melanin-Concentrating Hormone (MCH₁) receptor

Evaluation of the affinity of compounds for the human MCH₁ receptor wasaccomplished using4-(3,4,5-tritritiumbenzyloxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-oneand membranes prepared from stable CHO-K1 cells expressing the humanMCH₁ receptor obtained from Euroscreen (Batch 1138). Cell membranehomogenates (8.92 μg protein) were incubated for 60 min at 25° C. with1.4 nM of the [³H]-labeled compound in the absence or presence of thetest compound in 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding wasdetermined in the presence of 50 μM 1-(5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)urea.Following incubation, the samples were filtered rapidly under vacuumthrough Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, andwashed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting 9,9,0)using a Skatron cell harvester. The filters were counted forradioactivity in a liquid scintillation counter (Tri-Carb 2100TR,Packard) using a scintillation cocktail (Ultima Gold MV, Perkin Elmer).

The results are expressed as a percent inhibition of the controlradioligand specific binding. The IC₅₀ value (concentration causing ahalf-maximal inhibition of control specific binding) and Hillcoefficient (n_(H)) were determined by non-linear regression analysis ofthe competition curve using Hill equation curve fitting. The inhibitionconstant (K_(i)) was calculated from the Cheng Prusoff equation:(K_(i)=IC₅₀/(1+(L/K_(D))), where L=concentration of radioligand in theassay, and K_(D)=affinity of the radioligand for the receptor.

By methods as described above, the compounds listed in TABLE 1 weresynthesized and tested for biological activity. All of the compounds inTABLE 1 exhibited K_(i) of less than or equal to 3.5 μM in MCH₁ bindingassays I or II.

TABLE 1 Ex, Mass No. Structure Spec ¹H NMR Data 1

386 ¹H NMR (500 MHz, CD₃OD) δ 7.61-7.57 (2 × d, 2H), 7.47-7.46 (m, 3H),7.43-7.40 (m, 2H), 7.37-7.34 (m, 1H), 7.05 (dd, J = 8.3, 1.7 Hz, 1H),6.33 (dd, J = 7.5, 2.7 Hz, 1H), 6.16 (d, J = 2.6 Hz, 1H), 5.19 (s, 2H),4.57 (s, 2H), 3.73 (s, 3H), 3.67 (t, J = 6.2 Hz, 2H), 3.20 (t, J = 6.1Hz, 2H) 2

400 ¹H NMR (500 MHz, CD₃OD) δ 7.57 (dd, J = 7.6, 1.7 Hz, 2H), 7.47-7.46(m, 3H) 7.43-7.34 (m, 3H), 7.06 (dd, J = 8.4, 1.9 Hz, 1H), 6.29 (dd, J =7.6, 2.7 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 4.75 (d, J =14.3 Hz, 1H), 4.38 (d, J = 14.2 Hz, 1H), 3.90 (m, 1H), 3.73 (s, 3H),3.64-3.58 (m, 1H), 3.29-3.26 (m, 2H, partially masked by solvent), 3.13(s, 3H) 3

430 ¹H NMR (500 MHz, CD₃OD) δ 7.63 (dd, J = 7.6, 2.0 Hz, 2H), 7.51-7.50(m, 3H) 7.46-7.43 (m, 2H), 7.41-7.38 (m, 1H), 7.09 (dd, J = 8.3, 1.7 Hz,1H), 6.36 (dd, J = 7.6, 2.7 Hz, 1H), 6.18 (d, J = 2.7 Hz, 1H), 5.23 (s,2H), 4.82 (d, 1H, partially masked by solvent), 4.520 (d, J = 14.3 Hz,1H), 4.06-4.02 (m, 3H), 3.77 (s, 3H), 3.70-3.68 (m, 1H), 3.55-3.51 (m,2H), 3.33- 3.31 (m, 2H, partially masked by solvent) 4

497 ¹H NMR (500 MHz, CD₃OD) δ 7.62 (dd, J = 7.7, 1.9 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H) 7.46-7.44 (m, 2H), 7.41-7.35 (m, 4H), 7.06 (dd, J = 8.0,1.7 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 6.18 (s, 1H), 5.25 (s, 2H), 4.90(m, 1H, masked by solvent), 4.82 (s, 1H), 4.53 (d, J = 14.2 Hz, 2H),4.09 (t, J = 6.5 Hz, 1H), 3.91 (t, J = 6.4 Hz, 1H), 3.89-3.86 (m, 2H),3.77 (s, 3H), 3.20-3.18 (m, 2H), 3.05-3.03 (m, 1H), 2.99-2.97 (m, 1H),2.12-2.10 (m, 2H), 2.08-2.05 (m, 2H) 5

468 ¹H NMR (300 MHz, CD₃OD) δ 7.48 (d, J = 7.5 Hz, 1H), 7.40-7.24 (m,7H), 6.87 (dd, J = 8.3, 1.9 Hz, 1H), 6.19 (dd, J = 7.6, 2.7 Hz, 1H),6.03 (d, J = 2.7 Hz, 1H), 5.08 (s, 2H), 3.96 (s, 2H), 3.58 (s, 3H), 3.37(q, J = 9.7 Hz, 2H), 3.15-3.14 (m, 2H, partially masked by solvent),2.87 (t, J = 5.5 Hz, 2H) 6

482 ¹H NMR (500 MHz, CD₃OD) δ 7.66 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.6Hz, 1H), 7.52- 7.51 (m, 3H), 7.48-7.45 (m, 2H), 7.43 (d, J = 7.2 Hz,1H), 7.11 (dd, J = 8.3, 1.7 Hz, 1H), 6.36 (dd, J = 7.6, 2.7 Hz, 1H),6.19 (d, J = 2.7 Hz, 1H), 5.24 (s, 2H), 4.96 (m, 6H, masked by solvent),3.79-3.74 (m, 5H), 3.03-3.02 (m, 2H) 7

454 ¹H NMR (500 MHz, CD₃OD) δ 7.77 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.2Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.50 (s,1H), 7.09 (dd, J = 8.3, 1.8 Hz, 1H), 6.38 (dd, J = 7.6, 2.7 Hz, 1H),6.17 (d, J = 2.7 Hz, 1H), 5.33 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 3.71(t, J = 6.2 Hz, 2H), 3.24 (t, J = 6.1 Hz, 2H) 8

420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (br s, 2H), 7.57 (m, 2H), 7.51 (s,5H), 6.99 (d, J = 7.8 Hz, 1H), 6.12 (dd, J = 7.8, 2.7 Hz, 1H), 5.99 (d,J = 2.7 Hz, 1H), 5.16 (s, 2H), 4.33 (br s, 2H), 3.68 (s, 3H), 3.52-3.48(m, 2H), 3.12- 3.08 (m, 2H) 9

384 ¹H NMR (500 MHz, CD₃OD) δ 7.70 (d, J = 6.9 Hz, 1H), 7.62 (d, J = 8.3Hz, 1H), 7.52 (s, 1H), 7.33-7.26 (m, 4H), 7.22 (t, J = 7.2 Hz, 1H), 7.09(dd, J = 8.3, 1.6 Hz, 1H), 6.59-6.56 (m, 2H), 4.50 (s, 2H), 3.76 (s,3H), 3.70 (t, J = 6.2 Hz, 2H), 3.24 (t, J = 6.0 Hz, 2H), 3.04- 3.01 (m,2H), 2.98-2.95 (m, 2H) 10

424 ¹H NMR (500 MHz, CD₃OD) δ 7.95 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2Hz, 2H), 7.81 (d, J = 7.1 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.57 (s,1H), 7.14 (dd, J = 8.3, 1.3 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.87 (dd,J = 7.1, 1.7 Hz, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 3.68 (t, J = 6.1 Hz,2H), 3.22 (t, J = 6.1 Hz, 2H) 11

390 ¹H NMR (500 MHz, CD₃OD) δ 7.80-7.78 (m, 3H), 7.66 (d, J = 8.5 Hz,1H), 7.58-7.57 (m, 3H), 7.16 (dd, J = 8.3, 1.7 Hz, 1H), 6.94 (d, J = 1.8Hz, 1H), 6.87 (dd, J = 7.1, 1.9 Hz, 1H), 6.17 (d, J = 2.7 Hz, 1H), 4.53(s, 2H), 3.79 (s, 3H), 3.72 (t, J = 5.9 Hz, 2H), 3.25 (t, J = 5.9 Hz,2H) 12

424 ¹H NMR (500 MHz, CD₃OD) δ 7.80 (d, J = 7.0 Hz, 1H), 7.70 (s, 1H),7.68 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 2H), 7.13 (d, J = 7.0Hz, 1H), 6.73 (s, 1H), 6.61 (d, J = 7.2 Hz, 1H), 4.54 (s, 2H), 3.80 (s,3H), 3.72 (t, J = 6.0 Hz, 2H), 3.26 (t, J = 5.9 Hz, 2H) 13

386 ¹H NMR (500 MHz, CD₃OD) δ 7.59 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 9.0Hz, 1H), 7.48- 7.40 (m, 5H), 7.38-7.36 (m, 1H), 7.17 (dd, J = 8.5, 1.5Hz, 1H), 6.33 (dd, J = 7.5, 2.5 Hz, 1H), 6.16 (d, J = 2.5 Hz, 1H), 5.20(s, 2H), 4.45 (s, 2H), 3.77 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.21 (t,J = 6.0 Hz, 2H) 14

400 ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (s, 1H), 7.56-7.36 (m, 8H), 7.10(dd, J = 8.5, 1.5 Hz, 1H), 6.10 (dd, J = 7.5, 3.0 Hz, 1H), 5.97 (d, J =3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H),3.72 (s, 3H), 3.50 (m, 1H), 3.18 (m, 2H), 2.97 (s, 3H) 15

527 ¹H NMR (500 MHz, CD₃OD) δ 7.78-7.75 (m, 1H), 7.57-7.54 (m, 1H),7.49-7.37 (m, 6H), 7.04-7.01 (m, 1H), 6.55-6.52 (m, 1H), 6.33- 6.31 (m,1H), 5.26 (s, 2H), 4.80-4.73 (m, 2H), 4.49-4.48 (m, 2H), 3.94-3.93 (m,2H), 3.82- 3.72 (m, 2H), 3.69 (s, 3H), 3.58-3.57 (m, 2H), 3.20-3.14 (m,2H), 2.98-2.94 (m, 2H), 2.15- 1.99 (m, 4H) 16

471 ¹H NMR (500 MHz, CD₃OD) δ 7.75-7.71 (m, 1H), 7.59-7.55 (m, 1H),7.49-7.37 (m, 6H), 7.05-7.01 (m, 1H), 6.49-6.45 (m, 1H), 6.28- 6.26 (m,1H), 5.24 (s, 2H), 4.87 (br s, 1H), 4.69 (br s, 1H), 4.44-4.41 (m, 2H),4.11-4.07 (m, 1H), 3.85-3.82 (m, 1H), 3.70 (2 × s, 3H), 3.06-2.92 (m,2H), 2.97-2.94 (2 × s, 6H) 17

497 ¹H NMR (500 MHz, CD₃OD) δ 7.60 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 8.0Hz, 1H), 7.49- 7.35 (m, 6H), 7.06 (dd, J = 8.5, 1.5 Hz, 1H), 6.33 (dd, J= 7.5, 3.0 Hz, 1H), 6.16 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d, J =14.5 Hz, 1H), 4.54 (d, J = 14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m,1H), 3.75 (s, 3H), 3.68-3.65 (m, 1H), 3.54 (t, J = 7.0 Hz, 2H),3.49-3.45 (m, 2H), 3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H) 18

511 ¹H NMR (500 MHz, CD₃OD) δ 7.79-7.76 (m, 1H), 7.61-7.55 (m, 1H),7.49-7.36 (m, 6H), 7.05-7.02 (m, 1H), 6.55-6.52 (m, 1H), 6.33- 6.32 (m,1H), 5.26 (s, 2H), 4.06 (t, J = 5.5 Hz, 1H), 3.94 (t, J = 5.5 Hz, 1H),3.70-3.69 (m, 5H), 3.54-3.50 (m, 2H), 3.18-2.89 (m, 8H), 2.18-2.04 (m,4H) 19

483 ¹H NMR (500 MHz, CD₃OD) δ 7.75-7.72 (m, 1H) 7.63-7.55 (m, 1H),7.49-7.36 (m, 6H), 7.05-7.02 (m, 1H), 6.51-6.46 (m, 1H), 6.29- 6.27 (m,1H), 5.25 (s, 2H), 4.79-4.76 (m, 2H), 4.14-3.97 (m, 2H), 3.87-3.82 (m,1H), 3.71- 3.69 (m, 4H), 3.60-3.50 (m, 1H), 3.45-3.36 (m, 3H), 3.04-3.03(m, 1H), 2.94-2.92 (m, 1H), 2.52-2.36 (m, 1H), 2.18-2.00 (m, 1H) 20

483 ¹H NMR (500 MHz, CD₃OD) δ 7.82-7.79 (m, 1H), 7.66-7.56 (m, 1H),7.49-7.36 (m, 6H), 7.07-7.03 (m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd, J =5.0, 2.5 Hz, 1H), 5.28 (s, 2H), 4.82- 4.81 (m, 2H), 4.14-4.05 (m, 1H),3.97-3.95 (m, 1H), 3.71-3.69 (2 × s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94(m, 2H), 2.70-2.57 (m, 1H), 2.17-1.85 (m, 3H) 21

483 ¹H NMR (500 MHz, CD₃OD) δ 7.82-7.79 (m, 1H), 7.66-7.56 (m, 1H),7.49-7.36 (m, 6H), 7.07-7.03 (m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd, J =5.0, 2.5 Hz, 1H), 5.28 (s, 2H), 4.82- 4.81 (m, 2H), 4.14-4.05 (m, 1H),3.97-3.95 (m, 1H), 3.71-3.69 (2 × s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94(m, 2H), 2.70-2.57 (m, 1H), 2.17- 1.85 (m, 3H) 22

497 ¹H NMR (500 MHz, CD₃OD) δ 7.61-7.33 (m, 8H), 7.02-6.98 (m, 1H),6.29-6.27 (m, 1H), 6.12-6.11 (m, 1H), 5.17 (s, 2H), 4.79-4.76 (m, 2H),4.09-3.97 (m, 2H), 3.81-3.79 (m, 1H), 3.69-3.67 (m, 4H), 3.49-3.42 (m,1H), 3.22- 3.16 (m, 2H), 3.00 (m, 1H), 2.92-2.91 (m, 1H), 2.81-2.78 (2 ×s, 3H), 2.52-2.36 (m, 1H), 2.18- 2.00 (m, 1H) 23

497 ¹H NMR (500 MHz, CD₃OD) δ 7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30(dd, J = 7.5, 2.5 Hz, 1H), 6.13 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H),4.80-4.70 (m, 2H), 4.12-4.09 (m, 1H), 3.92- 3.90 (m, 1H), 3.78-3.72 (m,1H), 3.69-3.68 (2s, 3H), 3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H), 3.07-3.00(m, 2H), 2.96-2.94 (2s, 3H), 2.79-2.65 (m, 1H), 2.21-2.09 (m, 1H), 2.09-1.86 (m, 2H) 24

497 ¹H NMR (500 MHz, CD₃OD) δ 7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30(dd, J = 7.5, 2.5 Hz, 1H), 6.13 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H),4.80-4.70 (m, 2H), 4.12-4.09 (m, 1H), 3.92- 3.90 (m, 1H), 3.78-3.72 (m,1H), 3.69-3.68 (2s, 3H), 3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H), 3.07-3.00(m, 2H), 2.96-2.94 (2 × s, 3H), 2.79-2.65 (m, 1H), 2.21-2.09 (m, 1H),2.09- 1.86 (m, 2H) 25

388 ¹H NMR (500 MHz, CD₃OD) δ 7.82-7.79 (m, 2H), 7.75 (d, J = 7.0 Hz,1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.29-7.25 (m,2H), 7.14 (dd, J = 8.5, 1.5 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.82 (dd,J = 7.0, 2.0 Hz, 1H), 4.77 (d, J = 14.0 Hz, 1H), 4.41 (d, J = 14.0 Hz,1H), 3.93-3.90 (m, 1H), 3.76 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H),3.15 (s, 3H) 26

438 ¹H NMR (500 MHz, CD₃OD) δ 7.95 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5Hz, 2H), 7.80 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57 (d, J= 1.5 Hz, 1H), 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H),6.87 (dd, J = 7.5, 2.0 Hz, 1H), 4.78 (d, J = 14.0 Hz, 1H), 4.41 (d, J =14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.77 (s, 3H), 3.66-3.60 (m, 1H), 3.27(m, 2H), 3.15 (s, 3H) 27

404 ¹H NMR (500 MHz, CD₃OD) δ 7.77-7.75 (m, 3H), 7.62 (d, J = 8.5 Hz,1H), 7.57 (d, J = 2.0 Hz, 1H), 7.56-7.54 (m, 2H), 7.15 (dd, J = 8.5, 2.0Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 7.0, 2.0 Hz, 1H), 4.78(d, J = 14.0 Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.77(s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15 (s, 3H) 28

422 ¹H NMR (500 MHz, CD₃OD) δ 7.76 (d, J = 7.0 Hz, 1H), 7.66-7.57 (m,2H), 7.57 (d, J = 2.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.15 (dd, J = 8.5, 2.0Hz, 1H), 6.84 (s, 1H), 6.73-6.71 (m, 1H), 4.77 (d, J = 14.0 Hz, 1H),4.41 (d, J = 14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.76 (s, 3H), 3.64-3.61(m, 1H), 3.27 (m, 2H), 3.15 (s, 3H) 29

418 ¹H NMR (500 MHz, CD₃OD) δ 7.72 (d, J = 7.0 Hz, 1H), 7.63-7.56 (m,3H), 7.15 (dd, J = 8.5, 1.5 Hz, 1H), 6.92 (dd, J = 8.5, 2.5 Hz, 1H),6.87 (dd, J = 13.0, 2.0 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J = 7.0 Hz, 1H),4.77 (d, J = 14.0 Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.94-3.90 (m, 1H),3.88 (s, 3H), 3.76 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15 (s,3H) 30

400 ¹H NMR (500 MHz, CD₃OD) δ 7.67-7.63 (m, 2H), 7.50-7.40 (m, 3H),7.43-7.35 (m, 3H), 7.08 (dd, J = 8.3, 1.6 Hz, 1H), 6.40 (dd, J = 7.5,2.6 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 5.22 (s, 2H), 4.81-4.80 (m, 1H),4.58 (d, J = 15.3 Hz, 1H), 3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.55- 3.49(m, 1H), 3.21-3.16 (m, 5H) 31

398 ¹H NMR (500 MHz, CD₃OD) δ 7.67-7.64 (m, 2H), 7.51 (d, J = 1.8 Hz,1H), 7.30-7.24 (m, 4H), 7.20-7.17 (m, 1H), 7.08 (dd, J = 8.4, 1.9 Hz,1H), 6.56 (dd, J = 6.9, 1.9 Hz, 1H), 6.53 (s, 1H), 4.85 (m, 1H), 4.49(d, J = 15.3 Hz, 1H), 3.89-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.50 (m,1H), 3.21-3.19 (m, 2H), 3.16 (s, 3H), 3.02- 2.99 (m, 2H), 2.96-2.93 (m,2H) 32

468 ¹H NMR (500 MHz, CD₃OD) δ 7.78-7.73 (m, 3H), 7.69-7.64 (m, 3H), 7.52(d, J = 1.8 Hz, 1H), 7.18-7.08 (m, 1H), 6.55-6.52 (m, 1H), 6.28 (d, J =2.6 Hz, 1H), 5.35 (s, 2H), 4.82- 4.80 (m, 1H), 4.50 (d, J = 15.4 Hz,1H), 3.89- 3.85 (m, 1H), 3.73 (s, 3H), 3.55-3.50 (m, 1H), 3.22-3.16 (m,5H) 33

434 ¹H NMR (500 MHz, CD₃OD) δ 7.83 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.3Hz, 1H), 7.50- 7.46 (m, 3H), 7.44-7.42 (m, 2H), 7.08 (dd, J = 8.3, 1.8Hz, 1H), 6.41 (dd, J = 7.6, 2.6 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 5.21(s, 2H), 4.86-4.84 (m, 1H), 4.49 (d, J = 15.4 Hz, 1H), 3.88-3.84 (m,1H), 3.72 (s, 3H), 3.55-3.50 (m, 1H), 3.21-3.16 (m, 5H) 34

401 ¹H NMR (500 MHz, CD₃OD) δ 8.90 (dd, J = 5.8, 1.8 Hz, 1H), 8.65(overlapping ddd, J = 7.9, 1.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.07(overlapping dd, J = 6.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.65 (d, J =6.4 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.07 (dd, J = 6.8, 1.8 Hz, 1H),6.63 (dd, J = 7.6, 2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 5.59 (s, 2H),4.80 (m, 1H), 4.50 (d, J = 15.3 Hz, 1H), 3.88-3.85 (m, 1H), 3.73 (s,3H), 3.55-3.50 (m, 1H), 3.21-3.16 (m, 5H) 35

421 ¹H NMR (500 MHz, CD₃OD) δ 8.61 (s, 1H), 7.77 (dd, J = 8.3, 3.8 Hz,1H), 7.64-7.62 (m, 3H), 7.47 (d, J = 1.6 Hz, 1H), 7.03 (dd, J = 8.4, 1.8Hz, 1H), 6.37 (dd, J = 7.6, 3.8 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 5.28(s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J = 6.1 Hz, 2H), 3.12 (t,J = 6.0 Hz, 2H) 36

435 ¹H NMR (500 MHz, CD₃OD) δ 8.68 (br s, 1H), 8.05 (dd, J = 8.0, 2.4Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.65 (d, J= 8.3 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.3, 1.8 Hz, 1H),6.53 (dd, J = 7.6, 1.7 Hz, 1H), 6.28 (d, J = 1.6 Hz, 1H), 5.36 (s, 2H),4.85-4.80 (m, 1H), 4.49 (d, J = 15.3 Hz, 1H), 3.89-3.84 (m, 1H), 3.72(s, 3H), 3.53-3.47 (m, 1H), 3.22-3.19 (m, 2H), 3.16 (s, 3H) 37

404 ¹H NMR (500 MHz, DMSO-d₆) δ 11.0 (br s, 1H), 7.83 (dd, J = 6.8, 1.9Hz, 2H), 7.76 (d, J = 7.1 Hz, 1H), 7.62-7.57 (m, 4H), 7.07 (dd, J = 8.3,1.8 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 1H), 6.69 (dd, J = 7.2, 2.1 Hz,1H), 4.79 (d, J = 15.2 Hz, 1H), 4.44 (dd, J = 15.2, 6.0 Hz, 1H),3.74-3.68 (m, 4H), 3.48-3.38 (m, 1H), 3.10-2.99 (m, 5H) 38

390 ¹H NMR (500 MHz, CD₃OD) δ 7.78-7.75 (m, 3H), 7.67 (d, J = 8.3 Hz,1H), 7.55-7.53 (m, 3H), 7.13 (dd, J = 8.3, 1.8 Hz, 1H), 6.91 (d, J = 1.9Hz, 1H), 6.84 (dd, J = 7.1, 2.0 Hz, 1H), 4.56 (s, 2H), 3.74 (s, 3H),3.61 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 6.0 Hz, 2H) 39

424 ¹H NMR (300 MHz, CD₃OD) δ 7.97 (d, J = 8.1 Hz, 2H), 7.87-7.80 (m,3H), 7.68 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.14 (dd, J =8.3, 1.8 Hz, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.87 (dd, J = 7.2, 1.8 Hz,1H), 4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J = 6.0 Hz, 2H), 3.14 (t, J =6.0 Hz, 2H) 40

438 ¹H NMR (500 MHz, CD₃OD) δ 7.96 (d, J = 8.2 Hz, 2H), 7.85-7.83 (m,3H), 7.68 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.16 (dd, J =8.3, 1.7 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.90 (dd, J = 7.1, 1.9 Hz,1H), 4.87-4.86 (m, 1H), 4.51 (d, J = 15.3 Hz, 1H), 3.90-3.86 (m, 1H),3.74 (s, 3H), 3.57-3.51 (m, 1H), 3.23- 3.20 (m, 2H), 3.17 (s, 3H) 41

438 ¹H NMR (500 MHz, CD₃OD) δ 7.77 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.65 (overlapping dd, J = 1.1 Hz, 1H), 7.58 (d, J = 1.7 Hz,1H), 7.49 (s, 2H), 7.16 (dd, J = 8.3, 1.8 Hz, 1H), 6.70 (d, J = 1.5 Hz,1H), 6.62 (dd, J = 7.0, 1.9 Hz, 1H), 4.86 (m, 1H), 4.50 (d, J = 15.3 Hz,1H), 3.89-3.85 (m, 1H), 3.74 (s, 3H), 3.56-3.55 (m, 1H), 3.23-3.20 (m,2H), 3.16 (s, 3H) 42

386 ¹H NMR (500 MHz, DMSO-d₆) δ 9.71 (br s, 2H), 7.56 (d, J = 7.6 Hz,1H), 7.54 (d, J = 8.3 Hz, 1H), 7.50-7.47 (m, 3H), 7.44-7.41 (m, 2H),7.38-7.37 (m, 1H), 6.99 (dd, J = 8.3, 1.8 Hz, 1H), 6.11 (dd, J = 7.6,2.8 Hz, 1H), 5.97 (d, J = 2.6 Hz, 1H), 5.15 (s, 2H), 4.45 (s, 2H), 3.81(s, 3H), 3.42-3.41 (m, 2H), 2.98-2.97 (m, 2H) 43

430 ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.5Hz, 1H), 7.47- 7.46 (m, 3H), 7.42-7.39 (m, 2H), 7.36 (d, J = 7.1 Hz,1H), 7.06 (dd, J = 8.3, 1.8 Hz, 1H), 6.33 (dd, J = 7.6, 2.6 Hz, 1H),6.15 (d, J = 2.6 Hz, 1H), 5.19 (s, 2H), 4.81-4.79 (m, 1H), 4.59 (d, J =15.3 Hz, 1H), 4.01 (t, J = 5.1 Hz, 2H), 3.97-3.94 (m, 1H), 3.73 (s, 3H),3.58-3.50 (m, 3H), 3.21-3.16 (m, 2H) 44

497 ¹H NMR (500 MHz, CD₃OD) δ 7.86 (d, J = 7.5 Hz, 1H), 7.62 (dd, J =8.2, 2.7 Hz, 1H), 7.51-7.50 (m, 3H), 7.46-7.43 (m, 2H), 7.41-7.40 (m,1H), 7.08-7.06 (m, 1H), 6.63 (dd, J = 7.8, 2.6 Hz, 1H), 6.40 (d, J = 1.4Hz, 1H), 5.31 (s, 2H), 4.93 (s, 1.3H), 4.77 (s, 0.7H), 4.56-4.55 (m,2H), 4.04- 4.02 (m, 0.6H), 3.81-3.78 (m, 3.4H), 3.76 (s, 3H), 3.24-3.19(m, 2H), 2.79-2.97 (m, 1.3H), 2.92 2.85 (m, 0.7H), 2.22-2.19 (m, 2H),2.11-2.19 (m, 2H) 45

483 ¹H NMR (500 MHz, CD₃OD) δ 7.79 (dd, J = 7.5, 1.4 Hz, 1H), 7.47 (d, J= 8.3 Hz, 1H), 7.49-7.46 (m, 3H), 7.44-7.46 (m, 2H), 7.39- 7.36 (m, 1H),7.04 (dd, J = 8.3, 1.6 Hz, 1H), 6.57-6.55 (m, 1H), 6.34 (d, J = 2.5 Hz,1H), 5.27 (s, 2H), 4.96-4.87 (m, 2H), 3.90-8.86 (m, 2H), 3.77 (s, 3H),3.48-3.34 (m, 3H), 3.00-2.86 (m, 2H), 2.67-2.61 (m, 1H), 2.17-2.02 (m,3H) 46

386 ¹H NMR (500 MHz, CD₃OD) δ 7.66 (d, J = 7.5 Hz, 1H), 7.57-7.52 (m,2H), 7.46 (d, J = 7.7 Hz, 2H), 7.41 (overlapping dd, J = 7.3 Hz, 2H),7.36 (d, J = 7.5 Hz, 1H), 7.19 (dd, J = 8.6, 2.0 Hz, 1H), 6.42 (dd, J =7.5, 2.7 Hz, 1H), 6.22 (d, J = 2.6 Hz, 1H), 5.22 (s, 2H), 4.55 (s, 2H),3.75 (s, 3H), 3.58 (t, J = 6.0 Hz, 2H), 3.10 (t, J = 6.0 Hz, 2H) 47

400 ¹H NMR (500 MHz, CD₃OD) δ 7.56-7.53 (m, 2H), 7.51 (d, J = 1.8, 1H),7.46 (d, J = 7.3 Hz, 2H), 7.41 (overlapping dd, J = 7.4 Hz, 2H), 7.36(d, J = 7.2 Hz, 1H), 7.19 (dd, J = 8.6, 2.0 Hz, 1H), 6.27 (dd, J = 7.6,2.7 Hz, 1H), 6.11 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 4.64 (br s, 2H),3.75 (s, 3H), 3.67 (br s, 2H), 3.18-3.13 (m, 5H) 48

425 ¹H NMR (500 MHz, CD₃OD) δ 9.06 (s, 1H), 8.28 (dd, J = 8.4, 2.1 Hz,1H), 8.23 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 7.1 Hz, 1H), 7.64 (d, J =8.3 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.29(dd, J = Hz, 1H), 7.17 (dd, J = 8.3, 1.8 Hz, 1H), 4.50 (s, 2H), 3.76 (s,3H), 3.69 (t, J = 6.0 Hz, 2H), 3.22 (t, J = Hz, 2H) 49

405 ¹H NMR (500 MHz, CD₃OD) δ 8.70 (s, 1H), 8.00 (dt, J = 8.4, 2.8 Hz,1H), 7.91-7.88 (m, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.11(dd, J = 8.3, 1.7 Hz, 1H), 6.69 (dd, J = 7.5, 2.7 Hz, 1H), 6.45 (d, J =2.6 Hz, 1H), 5.46 (s, 2H), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J = 6.1Hz, 2H), 3.22 (t, J = 6.1 Hz, 2H) 50

426 ¹H NMR (500 MHz, CD₃OD) δ 8.54 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.9Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.60 (d, J= 1.5 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 7.2, 1.9 Hz, 1H),7.16 (dd, J = 8.3, 1.8 Hz, 1H), 4.50 (s, 2H), 3.77 (s, 3H), 3.69 (t, J =6.1 Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H) 51

421 ¹H NMR (300 MHz, CD₃OD) δ 8.61 (d, J = 2.1 Hz, 1H), 7.95 (dd, J =8.4, 2.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H),7.47 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 8.3, 1.8 Hz, 1H), 6.36 (dd, J =7.6, 2.2 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 5.28 (s, 2H), 4.48 (s, 2H),3.73 (s, 3H), 3.67 (t, J = 6.2 Hz, 2H), 3.02 (t, J =6.2 Hz, 2H) 52

435 ¹H NMR (300 MHz, CD₃OD) δ 8.60 (d, J = 2.0 Hz, 1H), 7.96-7.92 (m,1H), 7.61 (d, J = 7.7 Hz, 2H), 7.57 (d, J = 8.3 Hz, 1H), 7.47 (d, J =1.4 Hz, 7.06 (dd, J = 8.4, 1.7 Hz, 1H), 6.34 (dd, J = 7.6, 2.6Hz, 1H),6.12(d, J = 2.6Hz, 1H), 5.27 (s, 2H), 4.75 (d, J = 14.2 Hz, 1H), 4.38(d, J = 14.1 Hz, 1H), 3.95-3.85 (m, 1H), 3.73 (s, 3H), 3.63 (m, 1H),3.31 (m overlapping with solvent, 2H), 3.13 (s,3H) 53

387 ¹H NMR (300 MHz, CDCl₃) δ 8.88 (d, J = 5.2 Hz, 1H), 8.59 (dd, J =7.9, 1.5 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.01 (overlapping dd, J =6.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.48(d, J = 1.6 Hz, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.44 (dd, J = 7.6,2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 5.57 (s, 2H), 4.48 (s, 2H), 3.74(s, 3H), 3.68 (t, J = 6.2 Hz, 2H), 3.21 (t, J = 6.2 Hz, 2H 54

401 ¹H NMR (500 MHz, CD₃OD) δ 8.87 (d, J = 5.7 Hz, 1H), 8.58(overlapping dd, J = 8.2 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 8.00(overlapping dd, J = 6.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.59 (d, J =8.3 Hz, 1H), 7.49 (s, 1H), 7.07 (dd, J = 8.3, 1.7 Hz, 1H), 6.44 (dd, J =7.5, 2.6 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 5.56 (s, 2H), 4.76 (d, J =14.2 Hz, 1H), 4.40 (d, J = 14.2 Hz, 1H), 3.91 (m, 1H), 3.74 (s, 3H) 3.61(m, 1H), 3.29-3.17 (m overlapping with solvent, 2H), 3.13 (s, 3H) 55

387 ¹H NMR (500 MHz, CD₃OD) δ 8.89 (d, J = 5.4 Hz, 1H), 8.61(overlapping ddd, J = 8.0, 1.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.02(overlapping dd, J = 6.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.63 (d, J =8.4 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H),6.44 (dd, J = 7.6, 2.7 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 5.57 (s, 2H),4.56 (s, 2H), 3.73 (s, 2H), 3.73 (s, 3H), 3.60 (t, J = 6.0, 2H), 3.13(t, J = 6.0, 2H) 56

384 ¹H NMR (300 MHz, DMSO-d₆) δ 9.67 (s, 2H), 7.59-7.52 (m, 3H),7.35-7.27 (m, 4H), 7.24- 7.17 (m, 1H), 7.01 (dd, J = 7.4, 2.0 Hz, 1H),6.38-6.27 (m, 2H), 4.45 (s, 2H), 3.67 (s, 3H), 3.42 (t, J = 6.4 Hz, 2H),2.97-2.89 (m, 4H), 2.81-2.76 (m, 2H) 57

391 ¹H NMR (500 MHz, CD₃OD) δ 8.74 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.5Hz, 1H), 8.02 (dd, J = 8.7, 2.4 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.64(d, J = 8.3 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H),7.27 (dd, J = 8.5, 1.8 Hz, 1H), 7.15 (dd, J = 8.4, 1.8 Hz, 1H), 4.50 (s,2H), 3.75 (s, 3H), 3.68 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H) 59

419 ¹H NMR (500 MHz, CD₃OD) δ 8.65 (d, J = 2.6 Hz, 1H), 7.91(overlapping ddd, J = 9.6, 2.1 Hz, 1H), 7.83-7.20 (m, 2H), 7.61 (d, J =8.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.09 (dd, J = 8.4, 1.8 Hz, 1H),6.59 (dd, J = 7.5, 2.6 Hz, 1H), 6.36 (d, J = 2.6 Hz, 1H), 5.41 (s, 2H),4.76 (d, J = 14.2 Hz, 1H), 4.39 (d, J = 14.2 Hz, 1H), 3.94-3.82 (m, 2H),3.74 (s, 3H), 3.65- 3.58 (m, 2H), 3.13 (s, 3H) 60

405 ¹H NMR (500 MHz, CD₃OD) δ 8.72 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 7.9Hz, 1H), 7.99 (dd, J = 8.2, 2.2 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.61(d, J = 8.3 Hz, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H),7.19 (dd, J = 7.2, 1.8 Hz, 1H), 7.14 (dd, J = 8.3, 1.8 Hz, 1H),4.80-4.72 (br m, 1H), 4.46-4.34 (m, 1H), 3.96-3.86 (m, 1H), 3.75 (s,3H), 3.65-3.55 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H) 61

483 ¹H NMR (300 MHz, D₂O) δ 7.50 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 7.7Hz, 1H), 7.42-7.31 (m, 6H), 6.96 (dd, J = 8.3, 1.6 Hz, 1H), 6.27 (dd, J= 7.7, 2.6 Hz, 1H), 6.10 (d, J = 2.6 Hz, 1H), 5.90 (s, 2H), 4.59 (br s,2H), 3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J = 5.7 Hz, 2H),3.18-3.05 (br m, 2H), 2.15-1.90 (m, 4H) 62

439 ¹H NMR (500 MHz, CD₃OD) δ 9.04 (s, 1H), 8.28 (dd, J = 8.7, 1.9 Hz,1H), 8.21 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.62 (d, J =8.3 Hz, 1H), 7.58 (d, J = 1.3 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.24(dd, J = 7.1, 1.9 Hz, 1H), 7.15 (dd, J = 8.3, 1.7 Hz, 1H), 4.80-4.71 (brm, 1H), 4.44-4.35 (br m, 1H), 3.96-3.86 (br m, 1H), 3.75 (s, 3H),3.67-3.57 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H) 63

372 ¹H NMR (500 MHz, CD₃OD) δ 8.47 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.58 (d, J= 1.6 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 7.1, 1.9 Hz, 1H),7.15 (dd, J = 8.3, 1.9 Hz, 1H), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J =6.2 Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 2.85 (s, 3H) 64

386 ¹H NMR (300 MHz, DMSO-d₆) δ 10.9 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H),7.85 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 1.5 Hz,1H), 7.56 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.7 Hz, 1H), 7.14-7.11 (m,2H), 4.65 (d, J = 12.1 Hz, 1H), 4.31 (dd, J = 14.2, 7.5 Hz, 1H), 3.81-3.74 (m, 1H), 3.71 (s, 3H), 3.55-3.45 (m, 1H), 3.26-3.15 (m, 2H), 2.98(s, 3H), 2.72 (s, 3H) 65

404 ¹H NMR (300 MHz, DMSO-d₆) δ 9.56 (br s, 2H), 7.64 (d, J = 7.1 Hz,1H), 7.62-7.55 (m, 2H), 7.47 (dd, J = 8.4, 6.9 Hz, 1H), 7.12-7.06 (m,2H), 6.90 (overlapping ddd, J = 8.4, 2.4 Hz, 1H), 6.55 (d, J = 1.6 Hz,1H), 6.47 (dd, J = 7.1, 1.8 Hz, 1H), 4.37-4.30 (br m, 2H), 3.81 (s, 3H),3.69 (s, 3H), 3.56-3.45 (br m, 2H), 3.10 (t, J = 5.5 Hz, 2H) 66

418 ¹H NMR (300 MHz, DMSO-d₆) δ 10.83 (br s, 1H), 7.65 (d, J = 7.1 Hz,1H), 7.61 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.46 (dd, J =8.4, 6.9 Hz, 1H), 7.12-7.10 (m, 1H), 7.08 (d, J = 1.4 Hz, 1H), 6.91(overlapping ddd, J = 8.4, 2.4 Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 6.48(dd, J = 7.1, 1.6 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.30 (dd, J =14.2, 7.5 Hz, 1H), 3.86 (s, 3H), 3.80-3.76 (m, 1H), 3.75 (s, 3H),3.52-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.79 (d, J = 4.6 Hz, 3H) 67

469 ¹H NMR (500 MHz, D₂O) δ 7.56-7.53 (m, 2H), 7.48-7.40 (m, 6H), 7.02(dd, J = 8.4, 1.4 Hz, 1H), 6.33 (dd, J = 7.5, 2.4 Hz, 1H), 6.17 (d, J =2.4 Hz, 1H), 5.16 (s, 2H), 4.63 (br s, 2H), 4.09-3.79 (br m, 2H),3.69-3.53 (m, 6H), 3.26-3.23 (m, 2H), 3.14 (t, J = 12.8 Hz, 2H), 2.49(d, J = 1.3 Hz, 2H), 2.16-2.04 (m, 2H) 68

483 ¹H NMR (500 MHz, D₂O) δ 7.56-7.52 (m, 2H), 7.48-7.38 (m, 6H), 7.02(dd, J = 8.3, 1.6 Hz, 1H), 6.33 (dd, J = 7.5, 2.6 Hz, 1H), 6.16 (d, J =2.5 Hz, 1H), 5.16 (s, 2H), 4.63 (s, 2H), 3.85-3.83 (m, 2H), 3.74-3.71(m, 2H), 3.62 (s, 3H), 3.26-3.14 (m, 5H), 2.89 (s, 3H), 2.55-2.50 (m,2H), 2.19-2.12 (m, 2H) 69

425 ¹H NMR (300 MHz, CD₃OD) δ 9.10 (d, J = 2.0 Hz, 1H), 8.41 (dd, J =8.2, 1.7 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H),7.61 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 8.3,1.9 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.89 (dd, J = 7.1, 2.0 Hz, 1H),4.49 (s, 2H), 3.76 (s, 3H), 3.68 (t, J = 6.2 Hz, 2H), 3.22 (t, J = 6.2Hz, 2H) 70

439 ¹H NMR (500 MHz, CD₃OD) δ 9.09 (d, J = 1.7 Hz, 1H), 8.42 (dd, J =8.1, 2.0 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H),7.62 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.3,1.8 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.89 (dd, J = 7.1, 2.0 Hz, 1H),4.79-4.37 (br m, 2H), 3.90-3.60 (br m, 5H), 3.30 (br m, 2H), 3.14 (s,3H) 71

411 ¹H NMR (500 MHz, CD₃OD) δ 9.04 (s, 1H), 8.28 (dd, J = 8.3, 2.2 Hz,1H), 8.22 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.62 (d, J =8.3 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.24(dd, J = 7.1, 2.0 Hz, 1H), 7.11 (dd, J = 8.3, 2.0 Hz, 1H), 4.49 (s, 2H),3.65 (t, J = 6.2 Hz, 2H), 3.21 (t, J = 6.2 Hz, 2H) 72

412 ¹H NMR (300 MHz, CD₃OD) δ 8.52 (d, J = 8.9 Hz, 1H), 8.28 (d, J = 8.9Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.48 (d, J= 1.5 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.33 (dd, J = 7.2, 2.0 Hz, 1H),7.14 (dd, J = 7.4, 2.0 Hz, 1H), 4.49 (s, 2H), 3.65 (t, J = 6.2 Hz, 2H),3.21 (t, J = 6.2 Hz, 2H) 73

426 ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 9.37 (br s, 2H), 7.90 (d,J = 7.2 Hz, 1H), 7.62- 7.60 (m, 2H), 7.13 (d, J = 1.9 Hz, 1H), 7.10 (dd,J = 8.3, 1.7 Hz, 1H), 6.88 (dd, J = 7.1, 2.0 Hz, 1H), 4.38-4.34 (br m,2H), 3.70 (s, 3H), 3.56-3.50 (br m, 2H), 3.11 (t, J = 5.8 Hz, 2H) 74

426 ¹H NMR (500 MHz, DMSO-d₆) δ 9.48 (s, 2H), 9.37 (br s, 2H), 7.89 (d,J = 7.2 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H),7.50 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 7.6, 1.9 Hz, 1H), 7.12 (dd, J =8.3, 1.8 Hz, 1H), 4.41-4.31 (br m, 2H), 3.71 (s, 3H), 3.51-3.48 (br m,2H), 3.10 (t, J = 5.6 Hz, 2H) 75

455 ¹H NMR (500 MHz,DMSO-d₆) δ 9.54 (br s, 2H), 8.89 (s, 1H), 8.19 (dd,J = 7.9, 1.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz,1H), 7.55 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H), 6.98 (dd, J =8.3, 1.8 Hz, 1H), 6.15 (dd, J = 7.5, 2.7 Hz, 1H), 6.02 (d, J = 2.7 Hz,1H), 5.35 (s, 2H), 4.35-4.30 (br m, 2H), 3.67 (s, 3H), 3.53-3.47 (br m,2H), 3.09 (t, J = 5.8 Hz, 2H) 76

455 ¹H NMR (300 MHz, CD₃OD) δ 8.93 (s, 1H), 8.23 (dd, J = 8.2, 2.1 Hz,1H), 7.82 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.59 (d, J =8.3 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.06 (dd, J = 8.3, 1.8 Hz, 1H),6.47 (dd, J = 7.5, 2.7 Hz, 1H), 6.20 (d, J = 2.6 Hz, 1H), 5.42 (s, 2H),4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t, J = 6.1 Hz, 2H), 3.20 (t, J = 6.1Hz, 2H) 77

387 ¹H NMR (500 MHz, DMSO-d₆) δ 9.23 (s, 2H), 7.96 (d, J = 2.8 Hz, 1H),7.59 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.51-7.48 (m, 2H),7.46-7.42 (m, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.13 (dd, J = 8.4, 1.7 Hz,1H), 6.51 (d, J = 2.8 Hz, 1H), 5.22 (s, 2H), 4.34 (s, 2H), 3.69 (s, 3H),3.52 (t, J = 5.8 Hz, 2H), 3.09 (t, J = 5.8 Hz, 2H) 78

425 ¹H NMR (300 MHz, DMSO-d₆) δ 9.37 (s, 2H), 8.56 (d, J = 2.2 Hz, 1H),8.13 (d, J = Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 1.6 Hz,1H), 7.61 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.25 (dd, J =8.4, 1.8 Hz, 1H), 4.36 (s, 2H), 3.70 (s, 3H), 3.58-3.48 (br m, 2H), 3.11(t, J = 5.7 Hz, 2H) 79

391 ¹H NMR (500 MHz, CD₃OD) δ 8.73 (dd, J = 2.4, 0.6 Hz, 1H), 8.03 (dd,J = 8.5, 0.5 Hz, 1H), 8.00 (dd, J = 8.5, 2.4 Hz, 1H), 7.80 (d, J = 7.1Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.31 (d, J= 1.7 Hz, 1H), 7.19 (dd, J = 7.1, 2.0 Hz, 1H), 7.14 (dd, J = 8.4, 1.8Hz, 1H), 4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J = 6.1 Hz, 2H), 3.14 (t,J = 6.1 Hz, 2H) 80

405 ¹H NMR (500 MHz, CD₃OD) δ 8.73 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 8.5Hz, 1H) 7.99 (dd, J = 8.5, 2.3 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.67(d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.19 (dd, J= 7.1, 1.8 Hz, 1H), 7.15 (dd, J = 8.3, 1.7 Hz, 1H), 4.65 (br s, 2H),3.74 (m, 5H), 3.21 (t, J = 5.7 Hz, 2H), 3.17 (s, 3H) 81

425 ¹H NMR (500 MHz, CD₃OD) δ 9.05 (s, 1H), 8.28 (dd, J = 8.3, 2.2 Hz,1H), 8.22 (d, J = 8.3, Hz, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.67 (d, J =8.4 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.25(dd, J = 7.2, 2.0 Hz, 1H), 7.15 (dd, J = 8.4, 1.8 Hz, 1H), 4.57 (s, 2H),3.74 (s, 3H), 3.62 (t, J = 6.1 Hz, 2H), 3.15 (t, J = 5.9 Hz, 2H) 82

439 ¹H NMR (500 MHz, CD₃OD) δ 9.05 (s, 1H), 8.28 (dd, J = 8.3, 2.1 Hz,1H) 8.22 (d, J = 8.4, Hz, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.68 (d, J =8.3 Hz, 1H), 7.59 (d, J = 1.6, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.25 (dd,J = 7.2, 1.9 Hz, 1H), 7.16 (dd, J = 8.3, 1.8 Hz, 1H), 4.87 (s, 1H), 4.51(s, 1H), 3.87 (s, 1H), 3.75 (br s, 3H), 3.55 (br s, 1H), 3.21-3.17 (m,5H) 84

405 ¹H NMR (500 MHz, CD₃OD) δ 8.51 (s, 1H), 7.72-7.59 (m, 4H), 7.46 (d,J = 1.0 Hz, 1H), 7.05 (dd, J = 8.3, 1.5 Hz, 1H), 6.32 (dd, J = 7.6, 2.6Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 5.26 (s, 2H), 4.54 (s, 2H), 3.71 (s,3H), 3.60 (t, J = 6.0 Hz, 2H), 3.12 (t, J = 5.8 Hz, 2H) 85

419 ¹H NMR (500 MHz, CD₃OD) δ 8.51 (d, J = 2.6 Hz, 1H), 7.72-7.59 (m,4H), 7.47 (s, 1H), 7.06 (dd, J = 8.3, 1.7 Hz, 1H), 6.32 (dd, J = 7.6,2.6 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 5.26 (s, 2H), 4.68 (m, 2H), 3.71(m, SH), 3.18 (t, J = 5.9 Hz, 2H), 3.15 (s, 3H) 86

425 ¹H NMR (500 MHz, CD₃OD) δ 9.10 (d, J = 1.9 Hz, 1H), 8.41 (dd, J =8.2, 2.2 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H),7.68 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.15 (dd, J = 8.3,1.8 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.89 (dd, J = 7.1, 2.0 Hz, 1H),4.57 (br m, 2H), 3.75 (s, 3H), 3.62 (br m, 2H), 3.15 (br m, 2H) 87

411 ¹H NMR (500 MHz, CD₃OD) δ 9.05 (s, 1H), 8.28 (dd, J = 8.4, 2.1 Hz,1H), 8.22 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.66 (d, J =8.4 Hz, 1H), 7.48 (d, J = 7.1 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.24(dd, J = 7.2, 1.9 Hz, 1H), 7.13 (dd, J = 8.4, 1.8 Hz, 1H), 4.50 (s, 2H),3.63 (t, J = 6.1 Hz, 2H), 3.14 (t, J = 6.1 Hz, 2H) 88

387 ¹H NMR (500 MHz, CD₃OD) δ 7.93 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.43 (overlappingdd, J = 7.8 Hz, 2H), 7.39 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.7Hz, 1H), 6.48 (d, J = 2.7 Hz, 1H), 5.22 (s, 2H), 4.54 (s, 2H), 3.71 (s,3H), 3.59 (t, J = 5.6 Hz, 2H), 3.12 (t, J = 5.9 Hz, 2H) 89

455 ¹H NMR (500 MHz, CD₃OD) δ 8.75 (s, 1H), 8.08 (d, J = 7.9 Hz, 1H),7.79 (d, J = 8.1 Hz, 1H), 7.53 (dd, J = 7.9, 2.0 Hz, 2H), 7.38 (d, J =1.7 Hz, 1H), 6.97 (dd, J = 8.4, 1.8 Hz, 1H), 6.25 (dd, J = 7.6, 2.7 Hz,1H), 6.08 (d, J = 2.6 Hz, 1H), 5.26 (s, 2H), 4.46 (s, 2H), 3.63 (s, 3H),3.51 (t, J = 6.1 Hz, 2H), 3.03 (t, J = 6.1 Hz, 2H) 90

371 ¹H NMR (500 MHz, CD₃OD) δ 8.59 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H),7.87 (d, J = 6.5 Hz, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 8.4 Hz,1H), 7.56 (d, J = 1.4 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.15-7.12 (m,2H), 4.57 (s, 2H), 3.74 (s, 3H), 3.61 (t, J = 6.0 Hz, 2H), 3.14 (t, J =6.1 Hz, 2H), 2.46 (s, 3H) 91

371 ¹H NMR (500 MHz, CD₃OD) δ 8.76 (d, J = 1.8 Hz, 1H), 8.34 (d, J = 6.9Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.67 (d, J= 8.3 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.17(dd, J = 8.3, 1.8 Hz, 1H), 7.04 (dd, J = 7.1, 2.1 Hz, 1H), 4.53 (s, 2H),3.79 (s, 3H), 3.71 (t, J = 6.2 Hz, 2H), 3.25 (t, J = 6.2 Hz, 2H), 2.61(s, 3H) 92

371 ¹H NMR (500 MHz, CD₃OD) δ 8.80 (d, J = 2.2 Hz, 1H), 8.12 (dd, J =8.1, 2.5 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H),7.52 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.10 (dd, J = 8.3,1.9 Hz, 1H), 6.93 (d, J = 1.8 Hz, 1H), 6.85 (dd, J = 7.1, 2.0 Hz, 1H),4.34 (s, 2H), 3.73 (s, 3H), 3.52 (t, J = 6.1 Hz, 2H), 3.10 (t, J = 6.1Hz, 2H), 2.62 (s, 3H) 93

371 ¹H NMR (500 MHz, CD₃OD) δ 8.80 (d, J = 8.1 Hz, 1H), 8.11 (dd, J =8.2, 2.5 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H),7.52 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.11 (dd, J = 8.3,1.8 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.85 (dd, J = 7.1, 2.0 Hz, 1H),4.40 (s, 2H), 3.71 (s, 3H), 3.46 (t, J = 5.9 Hz, 2H), 3.04 (t, J = 5.9Hz, 2H), 2.62 (s, 3H) 94

400 ¹H NMR (500 MHz, CD₃OD) δ 7.79 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.53 (s, 1H), 7.48-7.36 (m, 5H), 7.10 (d, J = 8.5 Hz, 1H), 6.55(d, J = 6.5 Hz, 1H), 6.33 (s, 1H), 5.27 (s, 2H), 4.98 (q, J = 6.5 Hz,1H), 3.76 (s, 3H), 3.67-3.59 (m, 2H), 3.13-3.08 (m, 2H), 1.76 (d, J =7.0 Hz, 3H) 95

414 ¹H NMR (500 MHz, CD₃OD) δ 7.58-7.55 (m, 2H), 7.47-7.34 (m, 6H), 6.99(d, J = 8.5, 1.0 Hz, 1H), 6.28 (dd, J = 7.5, 2.5 Hz, 1H), 6.11 (d, J =2.5 Hz, 1H), 5.18 (s, 2H), 4.27 (q, J = 6.5 Hz, 1H), 3.69 (s, 3H),3.36-3.33 (m, 1H), 3.10-2.96 (m, 2H), 2.84-2.80 (m, 1H), 2.65 (s, 3H),1.51 (d, J = 6.5 Hz, 3H) 96

430 ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s, 2H), 7.66 (d, J = 2.0 Hz, 1H),7.59-7.56 (m, 2H), 7.49-7.37 (m, 5H), 7.08-7.05 (m, 1H), 6.14- 6.12 (m,1H), 5.99 (d, J = 2.5 Hz, 1H), 5.57 (s, 2H), 5.17 (s, 2H), 4.38 (m, 2H),3.55 (m, 2H), 3.45-3.40 (m, 2H), 3.13 (m, 2H), 1.08-1.05 (m, 3H) 97

356 ¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (s, 2H), 7.79 (dd, J = 8.0, 1.5 Hz,2H), 7.75 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.59 (d, J =8.5 Hz, 1H), 7.55-7.50 (m, 3H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 6.78 (d,J = 1.5 Hz, 1H), 6.70 (dd, J = 7.0, 2.0 Hz, 1H), 4.37 (m, 2H), 3.71 (s,3H), 3.54-3.53 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H) 98

370 ¹H NMR (500 MHz, DMSO-d₆) δ 10.46 (s, 1H), 7.80-7.74 (m, 3H), 7.63(s, 1H), 7.56-7.52 (m, 4H), 7.11 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 6.70(d, J = 7.0 Hz, 1H), 4.68-4.65 (m, 1H), 4.34-4.30 (m, 1H), 3.82-3.79 (m,1H), 3.71 (s, 3H), 3.53-3.51 (m, 1H), 3.20 (m, 2H), 3.00 (d, J = 4.0 Hz,3H) 99

404 ¹H NMR (500 MHz, CD₃OD) δ 7.72 (d, J = 7.0 Hz, 1H), 7.63-7.56 (m,3H), 7.14 (dd, J = 8.5, 1.5 Hz, 1H), 6.92 (dd, J = 8.5, 2.5 Hz, 1H),6.87 (dd, J = 13.0, 2.5 Hz, 1H), 6.84 (s, 1H), 6.77-6.75 (m, 1H), 4.50(s, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 3.22 (t,J = 6.0 Hz, 2H) 100

428 ¹H NMR (500 MHz, CDCl₃) δ 7.53-7.36 (m, 6H), 7.32-7.30 (m, 2H),7.06-7.00 (m, 1H), 6.09 (d, J = 3.0 Hz, 1H), 6.07-6.04 (m, 1H), 5.06 (s,2H), 4.82 (s, 1H), 4.67 (s, 1H), 4.03 (t, J = 5.5 Hz, 1H), 3.84 (t, J =5.5 Hz, 1H), 3.64 (s, 3H), 2.90 (t, J = 5.5 Hz, 1H), 2.84 (t, J = 5.5Hz, 1H), 2.24, 2.22 (2 × s, 3H) 101

447 ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d, J = 1.5 Hz, 1H), 7.54-7.46 (m,3H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.03 (ddd, J =20, 8.0, 1.5 Hz, 1H), 6.15-6.08 (m, 2H), 5.18 (s, 2H), 4.83, 4.70 (2 ×s, 2H), 4.04 (t, J = 5.5 Hz, 1H), 3.85 (t, J = 5.5 Hz, 1H), 3.65, 3.64(2 × s, 3H), 2.91 (t, J = 5.5 Hz, 1H), 2.85 (t, J = 5.5 Hz, 1H), 2.23,2.25 (2 × s, 3H) 102

392 ¹H NMR (500 MHz, CD₃OD) δ 7.67-7.65 (m, 2H), 7.50 (s, 1H), 7.09 (d,J = 8.5 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H), 6.10 (s, 1H), 4.58 (s, 2H),3.92 (d, J = 5.5 Hz, 2H), 3.75 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 3.15(d, J = 6.0 Hz, 2H), 1.92-1.74 (m, 6H), 1.39-1.19 (m, 5H) 103

392 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 2H), 7.55 (d, J = 8.5 Hz, 1H),7.52 (d, J = 7.5 Hz, 1H), 7.50 (s, 1H), 6.99 (dd, J = 8.5, 1.5 Hz, 1H),6.04 (dd, J = 7.5, 2.5 Hz, 1H), 5.85 (d, J = 2.5 Hz, 1H), 4.35 (s, 2H),3.82 (d, J = 6.0 Hz, 2H), 3.68 (s, 3H), 3.54-3.53 (m, 2H), 3.09 (t, J =5.5 Hz, 2H), 1.80-1.65 (m, 6H), 1.30- 1.01 (m, 5H) 104

406 ¹H NMR (500 MHz, DMSO-d₆) δ10.53 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H),7.51 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.00 (dd, J = 8.5,1.5 Hz, 1H), 6.04 (dd, J = 7.5, 2.5 Hz, 1H), 5.85 (d, J = 3.0 Hz, 1H),4.64 (d, J = 13 Hz, 1H), 4.30 (dd, J = 14, 7.5 Hz, 1H), 3.82 (d, J = 6.0Hz, 2H), 3.80-3.78 (m, 1H), 3.69 (s, 3H), 3.51-3.47 (m, 1H), 3.18 (t, J= 5.5 Hz, 2H), 2.98 (d, J = J = 4.5 Hz, 3H), 1.80-1.65 (m, 6H),1.30-1.01 (m, 5H) 105

416 ¹H NMR (500 MHz, DMSO-d₆) δ 9.48 (br s, 1H), 9.10 (br s, 1H), 7.56(overlapping dd, J = 8.5 Hz, 2H), 7.52 (s, 1H), 7.49-7.41 (m, 4H),7.40-7.36 (m, 1H), 7.01 (dd, J = 7.0, 1.5 Hz, 1H), 6.12 (dd, J = 7.5,1.5 Hz, 1H), 5.98 (d, J = 1.5 Hz, 1H), 5.72 (t, J = 3.3 Hz, 1H), 5.16(s, 2H), 4.89-4.82 (m, 1H), 4.07-4.01 (m, 1H), 3.80-3.71 (m, 1H), 3.72(s, 3H), 3.61-3.50 (m, 1H), 3.49-3.43 (m, 1H), 3.02-2.94 (m, 2H) 106

372 ¹H NMR (500 MHz, DMSO-d₆) δ 11.22 (s, 1H), 9.29 (br s, 2H), 7.54(dd, J = 12.0, 8.0 Hz, 2H), 7.50-7.41 (m, 4H), 7.40-7.33 (m, 2H), 6.96(dd, J = 8.0, 1.5 Hz, 1H), 6.09 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J =2.5 Hz, 1H), 5.15 (s, 2H), 4.38 (s, 2H), 3.50-3.42 (m, 2H) 3.00-2.92 (m,2H) 107

386 ¹H NMR (500 MHz, DMSO-d₆) δ 11.30 (s, 1H), 10.50-10.41 (m, 1H),7.58-7.52 (m, 2H), 7.49-7.40 (m, 4H), 7.39-7.35 (m, 2H), 6.96 (br d, J =8.0 Hz, 1H), 6.09 (br d, J = 7.5 Hz, 1H), 5.97 (br s, 1H), 5.15 (s, 2H),4.60 (br d, J = 15.0 Hz, 1H), 4.41 (dd, J = 15.0, 7.5 Hz, 1H), 3.78-3.71(m, 1H), 3.45-3.38 (m, 1H), 3.09- 2.98 (m, 5H) 108

410 ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H), 9.21 (br s, 2H), 8.01 (dJ = 8.3 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 7.0 Hz, 1H),7.58 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 1.5 Hz, 1H), 7.07 (dd, J = 8.0,1.5 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 7.0, 2.0 Hz, 1H),4.40 (s, 2H), 3.52-3.48 (m, 2H), 2.99 (t, J = 6.0 Hz, 2H) 109

424 ¹H NMR (500 MHz, DMSO-d₆) δ 11.36 (s, 1H), 10.35 (br s, 1H), 8.02(d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 7.0 Hz, 1H),7.59 (d, J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.07 (dd, J = 8.0, 1.5 Hz,1H), 6.87 (d, J = 1.5 Hz, 1H), 6.72 (d, J = 7.0, 1.5 Hz, 1H), 4.62 (brd, J = 16.0 Hz, 1H), 4.49-4.40 (m, 1H), 3.81-3.73 (m, 1H), 3.49-3.39 (m,1H), 3.12-3.00 (m, 5H) 110

414 ¹H NMR (500 MHz, DMSO-d₆) δ 9.59 (s, 1H), 7.58-7.51 (m, 3H),7.49-7.41 (m, 4H), 7.40-7.35 (m, 1H), 7.01 (dd, J = 8.5, 1.5 Hz, 1H),6.10 (dd, J = 7.5, 2.8 Hz, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.16 (s, 2H),3.80 (s, 3H), 3.52-3.48 (m, 2H), 2.99 (t, J = 6.0 Hz, 2H), 1.81 (s, 6H)111

469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (br s, 1H), 7.56 (d, J = 7.5 Hz,1H), 7.54-7.40 (m, 6H), 7.39-7.34 (m, 1H), 7.04-6.93 (m, 1H), 6.11 (dd,J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 2.5 Hz, 1H), 5.16 (s, 2H), 3.98-3.45(m, 11H), 3.39 (s, 1H), 3.30-3.21 (m, 2H), 2.25-2.10 (m, 1H), 2.05- 1.74(m, 2H), 1.73-1.60 (m, 1H) 112

420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (br s, 2H), 7.65 (d, J = 7.0 Hz,1H), 7.62 (d, J = 1.8 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.44 (d, J =8.0 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.0, 1.8 Hz, 1H),7.09 (dd, J = 8.5, 1.8 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.47 (dd, J =7.0, 2.0 Hz, 1H), 4.37 (br s, 2H), 3.87 (s, 3H), 3.70 (s, 3H), 3.57-3.52 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H) 113

434 ¹H NMR (500 MHz, DMSO-d₆) δ 10.15 (br s, 1H), 7.66 (d, J = 7.0 Hz,1H), 7.63 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.44 (d, J =8.5 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.5, 1.5 Hz, 1H),7.11 (dd, J = 8.0, 1.8 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.47 (dd, J =7.0, 2.0 Hz, 1H), 4.67 (d, J = 13.5 Hz, 1H), 4.33 (dd, J = 14.3, 6.0 Hz,1H), 3.87 (s, 3H), 3.86- 3.79 (m, 1H), 3.71 (s, 3H), 3.55-3.47 (m, 1H),3.24-3.15 (m, 2H), 3.01 (s, 3H) 114

388 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 8.88 (d, J = 5.0 Hz,2H), 7.58-7.52 (m, 4H), 6.99 (dd, J = 8.0, 1.8 Hz, 1H), 6.14 (dd, J =7.5, 2.5 Hz, 1H), 5.86 (d, J = 2.5 Hz, 1H), 5.33 (s, 2H), 4.36 (br s,2H), 3.68 (s, 3H), 3.57-3.52 (m, 2H), 3.11-3.05 (m, 2H) 115

426 ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (br s, 2H), 9.06 (s, 1H), 8.38 (s,1H), 8.19 (s, 1H), 8.05-7.94 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.56 (d,J = 8.0 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 6.99 (dd, J = 8.0, 1.5 Hz,1H), 6.13 (dd, J = 7.5, 2.5 Hz, 1H), 6.09 (d, J = 2.5 Hz, 1H), 5.33 (s,2H), 4.35 (br s, 2H), 3.69 (s, 3H), 3.56-3.50 (m, 2H), 3.12-3.05 (m, 2H)116

426 ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (br s, 2H), 8.84 (s, 1H), 8.37 (s,1H), 7.89-7.70 (m, 2H), 7.64-7.53 (m, 2H), 7.50 (s, 1H), 7.37-7.29 (m,1H), 7.03-6.97 (m, 1H), 6.20-6.09 (m, 2H), 5.41 (s, 2H), 4.35 (br s,2H), 3.69 (s, 3H), 3.58- 3.50 (m, 2H), 3.13-3.07 (m, 2H) 117

440 ¹H NMR (500 MHz, DMSO-d₆) 10.79 (br s, 1H), 8.87 (d, J = 6.5 Hz,1H), 8.41 (s, 1H), 7.90-7.78 (m, 2H), 7.61 (d, J = 7.5 Hz, 1H),7.53-7.49 (m, 2H), 7.42-7.35 (m, 1H), 7.00 (dd, J = 8.5, 1.5 Hz, 1H),6.15 (d, J = 2.5 Hz, 1H), 6.12 (dd, J = 7.5, 2.5 Hz, 1H), 5.43 (s, 2H),4.62 (d, J = 14.0 Hz, 1H), 4.29 (dd, J = 14.0, 7.5 Hz, 1H), 3.80-3.75(m, 1H), 3.69 (s, 3H), 3.55-3.46 (m, 1H), 3.23- 3.16 (m, 2H), 2.97 (s,3H) 118

428 ¹H NMR (500 MHz, DMSO-d₆) δ 7.56 (d, J = 7.5 Hz, 1H), 7.52-7.35 (m,7H), 6.94 (dd, J = 8.0, 1.5 Hz, 1H), 6.12-6.08 (m, 1H), 5.97 (d, J = 3.0Hz, 1H), 5.15 (s, 2H), 4.77-4.72 (m, 2H), 3.82-3.72 (m, 2H), 3.69-3.65(m, 3H), 3.82-2.78 (m, 1.3H), 2.71-2.68 (m, 0.7H), 2.16 (s, 3H) 119

467 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H),8.35 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.59-7.54 (m, 2H),7.28 (d, J = 1.5 Hz, 1H), 7.08-7.03 (m, 2H), 4.70 (s, 0.8H), 4.68 (s,1.2H), 3.88 (t, J = 5.5 Hz, 0.8H), 3.83 (t, J = 5.5 Hz, 1.2 H), 3.67 (s,3H), 2.97-2.91 (m, 1.2H), 2.86-2.81 (m, 0.8H), 2.15 (s, 1.8H), 2.13 (s,1.2H) 120

453 ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (br s, 1H), 9.15 (s, 1H),8.42-8.35 (m, 2H), 7.85 (d, J = 7.0 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H),7.61 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.5,1.5 Hz, 1H), 7.08 (dd, J = 7.5, 2.0 Hz, 1H), 4.70 (d, J = 12.5 Hz, 1H),4.32 (dd, J = 14.5, 8.0 Hz, 1H), 3.91-3.83 (m, 1H), 3.72 (s, 3H),3.52-3.43 (m, 1H), 3.41-3.30 (m, 2H), 3.24-3.16 (m, 2H), 1.38 (t, J =7.3 Hz, 3H) 121

467 ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br s, 1H), 9.15 (d, J = 2.0 Hz,1H), 8.42-8.35 (m, 2H), 7.85 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 1.5 Hz,1H), 7.62 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.14 (dd, J =8.5, 1.5 Hz, 1H), 7.08 (dd, J = 7.5, 2.0 Hz, 1H), 4.58 (d, J = 13.0 Hz,1H), 4.48-4.40 (m, 1H), 3.90-3.82 (m, 1H), 3.78-3.70 (m, 4H), 3.51-3.42(m, 1H), 3.38-3.15 (m, 2H), 1.45-1.36 (m, 6H) 122

386 ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (br s, 2H), 7.76 (d, J = 9.0 Hz,2H), 7.70 (d, J = 7.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.11-7.05 (m, 3H),6.73 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 7.0, 2.0 Hz, 1H), 4.51-4.45 (m,2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.48-3.42 (m, 2H), 2.99 (t, J = 6.0 Hz,2H) 123

402 ¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (br s, 2H), 7.77-7.71 (m, 3H),7.61-7.58 (m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.09 (dd, J = 8.5, 2.0 Hz,1H), 6.78 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 7.5, 2.0 Hz, 1H), 4.36 (brs, 2H), 3.70 (s, 3H), 3.56-3.51 (m, 2H), 3.10 (t, J = 5.5 Hz, 2H), 2.54(s, 3H) 124

402 ¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (br s, 2H), 7.75 (d, J = 8.5 Hz,2H), 7.73 (d, J = 7.3 Hz, 1H), 7.62-7.58 (m, 2H), 7.38 (d, J = 8.5 Hz,2H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.69 (dd,J = 7.3, 2.0 Hz, 1H), 4.49 (br s, 2H), 3.70 (s, 3H), 3.60-3.32 (m, 2H),2.99 (t, J = 5.5 Hz, 2H), 2.54 (s, 3H) 125

414 ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (br s, 2H), 7.57 (d, J = 7.5 Hz,1H), 7.53-7.50 (m, 2H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, 1H), 6.99 (dd,J = 8.0, 2.0 Hz, 1H), 6.11 (dd, J = 8.0, 2.5 Hz, 1H), 5.98 (d, J = 2.5Hz, 1H), 5.16 (s, 2H), 4.50 (br s, 2H), 3.70 (s, 3H), 2.89 (s, 2H), 1.42(s, 6H) 126

400 ¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (br s, 2H), 7.67 (d, J = 7.0 Hz,1H), 7.63 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.25 (d, J =8.5 Hz, 1H), 7.11 (dd, J = 8.5, 1.5 Hz, 1H),6.92 (d, J = 2.5 Hz, 1H),6.88 (dd, J = 8.5, 2.5 Hz, 1H), 6.37 (s, 1H), 6.34 (dd, J = 7.5, 1.5 Hz,1H), 4.89 (br s, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 3.49-3.43 (m, 2H),2.99 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H) 127

483 ¹H NMR (500 MHz,CD₃OD) δ 7.62-7.57 (m, 2H), 7.47-7.34 (m, 6H), 7.03(dd, J = 8.5, 1.5 Hz, 1H), 6.29 (dd, J = 7.5, 2.5 Hz, 1H), 6.12 (d, J =2.5 Hz, 1H), 5.18 (s, 2H), 4.55-4.43 (m, 2H), 3.72 (s, 3H), 3.38-3.14(m, 12H), 2.14 (m, 4H) 128

420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (br s, 2H), 7.65 (d, J = 7.0 Hz,1H), 7.61 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (d, J =8.5 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.5, 2.0 Hz, 1H),7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.47 (dd, J =7.0, 1.5 Hz, 1H), 4.49-4.47 (m, 2H), 3.87 (m, 3H), 3.69 (s, 3H),3.47-3.43 (m, 2H), 3.00-2.97 (m, 2H) 129

434 ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (br s, 1H), 7.65 (d, J = 7.0 Hz,1H), 7.62 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.44 (d, J =8.5 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 7.14-7.09 (m, 2H), 6.56 (d, J =1.5 Hz, 1H), 6.47 (dd, J = 7.0, 1.5 Hz, 1H), 4.79-4.76 (m, 1H),4.53-4.42 (m, 1H), 3.87 (s, 3H), 3.72-3.68 (m, 4H), 3.42-3.40 (m, 1H),3.08-3.06 (m, 2H), 3.00 (s, 3H) 130

469 ¹H NMR (500 MHz,CD₃OD) δ 7.59-7.56 (m, 2H), 7.47-7.45 (m, 3H),7.42-7.39 (m, 2H), 7.37-7.34 (m, 1H), 7.06 (dd, J = 8.5, 2.0 Hz, 1H),6.29 (dd, J = 7.5, 2.5 Hz, 1H), 6.12 (d, J = 3.0 Hz, 1H), 5.18 (s, 2H),4.70-4.49 (br m, 2H), 4.28-4.26 (m, 1H), 3.75-3.73 (m, 7H), 3.46-3.43(m, 2H), 3.34-3.33 (m, 2H), 2.46-2.43 (m, 1H), 2.21-2.08 (m, 2H),1.91-1.86 (m, 1H) 131

386 ¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (br s, 2H), 7.76 (d, J = 9.0 Hz,2H), 7.70 (d, J = 7.0 Hz, 1H), 7.60-7.57 (m, 2H), 7.09-7.06 (m, 3H),6.73 (d, J = 2.0 Hz, 1H), 6.68 (dd, J =7.5, 2.0 Hz, 1H), 4.37-4.35 (m,2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.54-3.53 (m, 2H), 3.10 (t, J = 6.0 Hz,2H) 132

400 ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (br s, 2H), 7.67 (d, J = 7.0 Hz,1H), 7.59 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.25 (d, J =8.5 Hz, 1H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H),6.88 (dd, J = 8.0, 2.5 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 6.34 (dd, J =7.0, 2.0 Hz, 1H), 4.36-4.34 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H),3.53-3.52 (m, 2H), 3.10 (t, J =6.0 Hz, 2H), 2.35 (s, 3H) 133

422 ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (br s, 2H), 8.11 (t, J = 58.0 Hz,1H), 7.78 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.60 (d, J =7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.22 (dd, J = 8.5, 1.5 Hz, 1H), 6.14(dd, J = 7.5, 2.5 Hz, 1H), 5.99 (d, J = 2.5 Hz, 1H), 5.16 (s, 2H), 4.52(m, 2H), 3.49-3.48 (m, 2H), 2.99 (m, 2H) 134

436 ¹H NMR (500 MHz, DMSO-d₆) δ 10.89 (br s, 1H), 8.15 (t, J = 58.0 Hz,1H), 7.82 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.60 (d, J =7.6 Hz, 1H), 7.47-7.36 (m, 5H), 7.23 (dd, J = 8.4, 1.5 Hz, 1H), 6.14(dd, J = 7.6, 2.7 Hz, 1H), 6.00 (d, J = 2.7 Hz, 1H), 5.16 (s, 2H), 4.77(m, 1H), 4.55 (m, 1H), 3.76-3.75 (m, 1H), 3.45-3.40 (m, 1H), 3.07-3.02(m, 5H) 135

404 ¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (s, 2H), 7.71 (d, J = 7.2 Hz, 1H),7.62-7.58 (m, 3H), 7.10 (dd, J = 8.3, 1.8 Hz, 1H), 7.01 (dd, J = 13.2,2.4 Hz, 1H), 6.94 (dd, J = 8.6, 2.3 Hz, 1H), 6.62 (s, 1H), 6.53-6.52 (m,1H), 4.48 (s, 2H), 3.95 (s, 3H), 3.69 (s, 3H), 3.45-3.44 (m, 2H),3.00-2.97 (m, 2H) 136

418 ¹H NMR (500 MHz, DMSO-d₆) δ 10.71 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H),7.63-7.59 (m, 3H), 7.11 (dd, J = 8.3, 1.6 Hz, 1H), 7.01 (dd, J = 13.2,2.4 Hz, 1H), 6.94 (dd, J = 8.7, 2.4 Hz, 1H), 6.62 (s, 1H), 6.53-6.52 (m,1H), 4.80-4.77 (m, 1H), 4.45-4.43 (m, 1H), 3.84 (s, 3H), 3.73 (br s,1H), 3.68 (s, 3H), 3.42-3.34 (m, 1H), 3.07-3.06 (m, 2H), 3.00 (s, 3H)137

426 ¹H NMR (500 MHz,CD₃OD) δ 8.81 (d, J = 7.0, 1.0 Hz, 1H), 8.38 (s,1H), 8.02-7.99 (m, 1H), 7.92 (d, J = 9.5 Hz, 1H), 7.66-7.62 (m, 2H),7.52-7.49 (m, 1H), 7.46 (s, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.33 (dd, J =7.5, 3.0 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 5.50 (s, 2H), 4.55 (s, 2H),3.72 (s, 3H), 3.60 (t, J = 6.0 Hz, 2H), 3.14-3.12 (m, 2H) 138

440 ¹H NMR (500 MHz, DMSO-d₆) δ 10.91 (br s, 1H), 8.86 (d, J = 6.0 Hz,1H), 8.39 (s, 1H), 7.87-7.79 (m, 2H), 7.61 (d, J = 7.5 Hz, 1H), 7.57 (d,J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.37-7.35 (m, 1H), 7.01 (dd, J = 8.5, 1.0Hz, 1H), 6.15-6.11 (m, 2H), 5.42 (s, 2H), 4.77 (d, J = 15.0 Hz, 1H),4.43 (dd, J = 14.0, 6.0 Hz, 1H), 3.80-3.77 (m, 1H), 3.66 (s, 3H),3.41-3.39 (m, 1H), 3.08- 3.04 (m, 2H), 2.99 (s, 3H) 139

426 ¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (br s, 2H), 9.01 (s, 1H), 8.33 (s,1H), 8.11 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H),7.61 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 1.6 Hz,1H), 7.00 (dd, J = 8.4, 1.7 Hz, 1H), 6.13 (dd, J = 7.6, 2.7 Hz, 1H),6.08 (d, J = 2.7 Hz, 1H), 5.31 (s, 2H), 4.46 (m, 2H), 3.67 (s, 3H), 3.44(m, 2H), 2.97 (t, J = 5.7 Hz, 2H) 140

418 ¹H NMR (300 MHz, CD₃OD) δ 7.53-7.33 (m, 7H), 7.27 (d, J = 10.5 Hz,1H), 7.28 (dd, J = 7.8, 2.4 Hz, 1H), 6.10 (d, J = 2.7 Hz, 1H), 5.17 (s,2H), 3.79 (br s, 2H), 3.67 (s, 3H), 3.03-3.00 (m, 4H), 2.64 (s, 3H) 141

404 ¹H NMR (500 MHz, DMSO-d₆) δ 9.56 (br s, 2H), 7.61 (d, J = 6.0 Hz,1H), 7.54 (d, J = 7.5 Hz, 1H), 7.50-7.37 (m, 6H), 6.14-6.12 (m, 1H),5.99 (s, 1H), 5.16 (s, 2H), 4.46 (br s, 2H), 3.67 (s, 3H), 3.43 (br m,2H), 2.94 (m, 2H) 142

414 ¹H NMR (500 MHz, DMSO-d₆) δ 7.57 (d, J = 7.5 Hz, 1H), 7.54-7.34 (m,7H), 6.97 (d, J = 8.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.0 Hz, 1H), 5.97 (s,1H), 5.16 (s, 2H), 3.67 (s, 3H), 3.45-3.18 (4H, overlapping with solventpeak), 3.26 (br m, 2H), 2.96 (m, 2H), 1.33 (br m, 3H) 143

428 ¹H NMR (500 MHz, DMSO-d₆) δ 10.50 (s, 1H), 7.56 (d, J = 4.5 Hz, 2H),7.52-7.38 (m, 6H), 7.01 (dd, J = 4.5, 1.0 Hz, 1H), 6.11 (dd, J = 4.5,1.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 4.60-4.53 (m, 2H), 3.78-3.70(m, 2H), 3.70 (s, 3H), 3.40-3.28 (m, 1H), 3.18-2.98 (m, 2H), 1.44-1.39(m, 6H) 144

472 ¹H NMR (500 MHz, CDCl₃) δ 7.48 (d, J = 8.5 Hz, 1H), 7.50-7.32 (m,7H), 6.99 (d, J = 8.5 Hz, 1H), 6.90 (s, 1H), 6.34 (d, J = 6.5 Hz, 1H),5.17 (s, 2H), 5.05-5.00 (m, 1H), 4.72-4.58 (m, 2H), 3.79 (br m, 2H),3.76 (s, 3H), 2.82 (m, 2H), 1.42-1.32 (m, 6H) 145

465 ¹H NMR (300 MHz, CD₃OD) δ 7.71 (d, J = 7.8 Hz, 1H), 7.63 (d, J =8.4, Hz, 1H), 7.53-7.30 (m, 6H), 7.05 (dd, J = 7.8, 1.2 Hz, 1H), 6.60(d, J = 7.6 Hz, 1H), 5.40 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.62-3.55(m, 2H), 3.22-3.02 (m, 2H) 146

372 ¹H NMR (500 MHz, CD₃OD) δ 7.65 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 8.2Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.42-7.36 (m, 4H), 7.03 (d, J = 8.5Hz, 1H), 6.39 (dd, J = 7.6, 2.5 Hz, 1H), 6.21 (d, J = 2.5 Hz, 1H), 5.21(s, 2H), 4.47 (s, 2H), 3.64 (t, J = 6.0 Hz, 2H), 3.20 (t, J = 6.1 Hz,2H) 147

400 ¹H NMR (300 MHz, CD₃OD) δ 7.83 (d, J = 7.5 Hz, 1H), 7.62-7.57 (m,2H), 7.45-7.40 (m, 5H), 7.09 (dd, J = 8.4, 1.6 Hz, 1H), 6.59 (dd, J =7.5, 2.3 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 5.28 (s, 2H), 4.49 (s, 2H),4.23 (q, J = 7.2 Hz, 2H), 3.68 (t, J = 6.1 Hz, 2H), 3.22 (t, J = 5.9 Hz,2H), 1.35 (t, J = 7.1 Hz, 3H)

As compounds that bind strongly to MCH₁, compounds of formula I areexpected to be effective in reducing obesity.

The present invention is not limited to the compounds found in the aboveexamples, and many other compounds falling within the scope of theinvention may also be prepared using the procedures set forth in theabove synthetic schemes. The preparation of additional compounds offormula (I) using these methods will be apparent to one of ordinaryskill in the chemical arts.

The invention has been described in detail with particular reference tosome embodiments thereof, but it will be understood by those skilled inthe art that variations and modifications can be effected within thespirit and scope of the invention.

1. A compound of formula I:

wherein R¹ is H or optionally substituted alkyl; R², R³, R⁴ are eachindependently selected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF₃,and —CN; G is —CR¹²R¹³—NR⁵— or —NR⁵—CR¹²R¹³; R⁵ is H, optionallysubstituted alkyl, optionally substituted heterocycle, —C(═O)—R⁶,—C(═O)-o-R⁷, or —C(═O)—NR¹⁹R²⁰; R⁶ and R⁷ are each optionallysubstituted alkyl or optionally substituted heterocycle; R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁹ and R²⁰ are each independently selected from H oroptionally substituted alkyl; R¹⁴ and R¹⁵ are each independently H orhalogen; Y is CH or N; L is —CH₂—O—, —CH₂CH₂—, —CH═CH— or a bond; and Bis aryl or heteroaryl or cycloalkyl; with the proviso that, when L is adirect bond, B cannot be unsubstituted heteroaryl or heteroarylmonosubstituted with fluorine.
 2. A compound according to claim 1wherein G is —CH₂—NR⁵—.
 3. A compound according to claim 1 wherein G is—NR⁵—CH₂—.
 4. A compound according to claim 1 wherein R⁵ is H.
 5. Acompound according to claim 1 wherein R⁵ is optionally substitutedalkyl.
 6. A compound according to claim 5 wherein R⁵ is selected frommethyl, ethyl, 2-propyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl and 2-oxo-2-(pyrrolidin-1-yl)ethyl,2-(pyrrolidin-1-yl)ethyl and (S)-pyrrolidin-2-ylmethyl.
 7. A compoundaccording to claim 1 wherein R⁵ is optionally substituted heterocycle.8. A compound according to claim 7 wherein R⁵ is selected frompiperidin-4-yl and 1-methylpiperidin-4-yl.
 9. A compound according toclaim 1 wherein R⁵ is —C(═O)—R⁶ or —C(═O)—O—R⁷.
 10. A compound accordingto claim 1 wherein R⁵ is —C(═O)—NR¹⁹R²⁰.
 11. A compound according toclaim 7 wherein R⁶ and R⁷ are each optionally substituted alkyl.
 12. Acompound according to claim 11 wherein R⁶ and R⁷ are selected frommethyl, 2-pyrrolidin-1-ylmethyl and dimethylaminomethyl.
 13. A compoundaccording to claim 7 wherein R⁶ and R⁷ are each optionally substitutedheterocycle.
 14. A compound according to claim 13 wherein R⁶ and R⁷ areselected from pyrrolidin-3-yl, (R)-pyrrolidin-2-yl, (S)-pyrrolidin-2-yl,1-methylpyrrolidin-3-yl, (R)-1-methylpyrrolidin-2-yl and(S)-1-methylpyrrolidin-2-yl.
 15. A compound according to claim 1 whereinR¹ is H.
 16. A compound according to claim 1 wherein R¹ is alkyl.
 17. Acompound according to claim 16 wherein R¹ is selected from methyl andethyl.
 18. A compound according to claim 1 wherein the compound has

the structure
 19. A compound according to claim 1 wherein the compoundhas

the structure
 20. A compound according to claim 1 wherein L is a bond.21. A compound according to claim 1 wherein L is —CH₂—O—.
 22. A compoundaccording to claim 1 wherein L is —CH₂CH₂—.
 23. A compound according toclaim 1 wherein L is —CH═CH—.
 24. A compound according to claim 1wherein B is aryl.
 25. A compound according to claim 24 wherein B isphenyl.
 26. A compound according to claim 1 wherein B is heteroaryl. 27.A compound according to claim 26 wherein B is pyridinyl.
 28. A compoundaccording to claim 27 wherein B is pyridin-2-yl.
 29. A compoundaccording to claim 27 wherein B is pyridin-3-yl.
 30. A compoundaccording to claim 26 wherein B is pyridazinyl.
 31. A compound accordingto claim 30 wherein B is pyridazin-3-yl.
 32. A compound according toclaim 26 wherein B is pyrimidinyl.
 33. A compound according to claim 32wherein B is pyrimidin-5-yl.
 34. A compound according to claim 32wherein B is pyrimidin-2-yl.
 35. A compound according to claim 1 whereinB is cycloalkyl.
 36. A compound according to claim 35 wherein B iscyclohexyl.
 37. A compound according to claim 1 wherein R², R³ and R⁴are each H.
 38. A compound according to claim 1 wherein two of R², R³and R⁴ are H, and the other of R², R³ and R⁴ is selected fromtrifluoromethyl, chloro, fluoro, methyl, methoxy and methylthio.
 39. Acompound according to claim 1 wherein one of R², R³ and R⁴ is H, anotherof R², R³ and R⁴ is Cl, and the third of R², R³ and R⁴ is F, Cl ormethoxy.
 40. A compound according to claim 1 wherein one of R², R³ andR⁴ is H, another of R², R³ and R⁴ is F, and the third of R², R³ and R⁴is methoxy.
 41. A compound according to claim 1 wherein one of R², R³and R⁴ is H, another of R², R³ and R⁴ is methoxy, and the third of R²,R³ and R⁴ is methyl.
 42. A compound according to claim 1 wherein B,together with R², R³ and R⁴, is selected from phenyl,4-trifluoromethylphenyl, 4-chlorophenyl, 2,4-dichlorophenyl,4-fluorophenyl, 4-chloro-2-fluorophenyl, 2-fluoro-4-methoxyphenyl,pyridin-2-yl, 5-chloropyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl,5-fluoropyridin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl,6-methylpyridazin-3-yl, 4-fluoro-2-methoxyphenyl,6-(trifluoromethyl)pyridin-3-yl, 2-(trifluoromethyl)pyrimidin-5-yl,5-(trifluoromethyl)pyrimidin-2-yl, 5-methylpyridin-2-yl,6-methylpyridin-3-yl, cyclohexyl, 4-chloro-2-methoxyphenyl,pyrimidin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-2-yl,4-methoxyphenyl, 4-methanethiophenyl and 4-methoxy-2-methylphenyl.
 43. Acompound according to claim 1 wherein the compound is selected from


44. A compound according to claim 1 wherein the compound is selectedfrom


45. A compound according to claim 1 wherein R¹ is substituted alkyl. 46.A compound according to claim 45 wherein R¹ is selected fromdifluoromethyl and ethoxymethyl.
 47. A compound according to claim 1wherein at least one of R⁸ and R⁹ is H.
 48. A compound according toclaim 1 wherein at least one of R⁸ and R⁹ is alkyl.
 49. A compoundaccording to claim 48 wherein at least one of R⁸ and R⁹ is methyl.
 50. Acompound according to claim 1 wherein R¹⁰ is alkyl.
 51. A compoundaccording to claim 50 wherein R¹⁰ is methyl.
 52. A compound according toclaim 1 wherein R¹⁰ is substituted alkyl.
 53. A compound according toclaim 52 wherein R¹⁰ is hydroxymethyl.
 54. A compound according to claim1 wherein R¹¹ is alkyl.
 55. A compound according to claim 54 wherein R¹¹is methyl.
 56. A compound according to claim 1 wherein R¹² is alkyl. 57.A compound according to claim 56 wherein R¹² is methyl.
 58. A compoundaccording to claim 1 wherein R¹³ is alkyl.
 59. A compound according toclaim 58 wherein R¹³ is methyl.
 60. A compound according to claim 1wherein R¹⁰, R¹¹, R¹² and R¹³ are each methyl.
 61. A compound accordingto claim 1 wherein R¹⁴ is H.
 62. A compound according to claim 1 whereinR¹⁴ is halogen.
 63. A compound according to claim 1 wherein G is—CH₂—NR⁵— or —NR⁵—CH₂—; R¹ and R⁵ are each independently H or methyl;R¹⁴ is H; R¹⁵ is H or halogen; B is phenyl or heteroaryl; and (a) when Lis —CH₂—O—, —CH₂CH₂—, or —CH═CH—; then R², R³, R⁴ are each independentlyselected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF₃, and —CN; or (b)when L is a direct bond, R² is selected from —O-alkyl, —S-alkyl, alkyl,Cl, Br, —CF₃ and —CN, and R³ and R⁴ are each independently selected fromH, —O-alkyl, —S-alkyl, alkyl, halo, —CF₃ and —CN.
 64. A compoundaccording to claim 1 wherein the compound is in a pharmaceuticallyacceptable salt form.
 65. A compound according to claim 64 wherein thesalt is an HCl salt.
 66. A pharmaceutical composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier,excipient or diluent therefore.
 67. A method of treating obesity,comprising administering to a patient in need of obesity reduction anobesity-reducing effective amount of a compound according to claim 1.68. A method of treating anxiety, comprising administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim
 1. 69. A method of treating depression,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound according to claim
 1. 70.A method of treating non-alcoholic fatty liver disease, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 1. 71. A method oftreating a disease or condition which is susceptible to treatment withan MCH₁ receptor modulator, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound accordingto claim 1.